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Lee JI, Park S, Park H, Lee Y, Park J, Lee D, Kim MJ, Choe KM. The matrix glycoprotein Papilin maintains the haematopoietic progenitor pool in Drosophila lymph glands. Development 2025; 152:dev204367. [PMID: 40094323 PMCID: PMC12045604 DOI: 10.1242/dev.204367] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Accepted: 02/14/2025] [Indexed: 03/19/2025]
Abstract
Differentiation of prohaemocytes, the precursors of Drosophila blood cells (haemocytes), and the release of haemocytes from the lymph gland, a major larval haematopoietic organ, are vital responses to wasp infestation or tissue degeneration. Although cells and extracellular matrix (ECM) in the lymph gland are known to play a crucial role in haemocyte differentiation, the underlying mechanisms remain unclear. Here, we show that the matrix glycoprotein Papilin (Ppn) is essential for maintaining the prohaemocyte population in lymph glands. In Ppn-depleted larvae, haemocyte differentiation increased with a reduction in the prohaemocyte-containing medullary zone, and lymph gland lobes dispersed prematurely. Ppn was synthesised by plasmatocytes, forming lamellae mainly in the medullary zone. Microbial infection or wasp infestation disrupted the Ppn meshwork within lymph glands. Ppn colocalised with collagen, laminin, nidogen and perlecan. Ppn depletion disrupted the ECM structure, including perlecan organisation. Phenotypes caused by Ppn depletion were partially rescued by perlecan overexpression or inactivation of the epidermal growth factor receptor pathway. Thus, Ppn is crucial for maintaining lymph gland architecture and regulating haemocyte differentiation, highlighting an intricate interaction between the ECM and signalling pathways in haematopoiesis.
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Affiliation(s)
- Jae-In Lee
- Department of Systems Biology, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, South Korea
| | - Sumin Park
- Department of Systems Biology, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, South Korea
| | - Hyunji Park
- Department of Systems Biology, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, South Korea
| | - Youngbin Lee
- Department of Systems Biology, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, South Korea
| | - JinYoung Park
- Department of Systems Biology, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, South Korea
| | - Donghoon Lee
- Department of Systems Biology, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, South Korea
| | - Moon Jong Kim
- Department of Life Science, Gachon University, Seongnam 13120, South Korea
| | - Kwang-Min Choe
- Department of Systems Biology, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, South Korea
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2
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Xu Q, Lu J, Gu X, Chi F, Zhao Y, Li F, Jiang X, Li B, Wei J. The parasitoid Exorista sorbillans exploits host silkworm encapsulation to build respiratory funnel for survival. INSECT BIOCHEMISTRY AND MOLECULAR BIOLOGY 2025; 177:104255. [PMID: 39742982 DOI: 10.1016/j.ibmb.2024.104255] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/15/2024] [Accepted: 12/29/2024] [Indexed: 01/04/2025]
Abstract
Insect parasitoids have evolved sophisticated strategies to evade or modulate host immunity for parasitic infections. The precise mechanisms by which parasitoids counteract host anti-parasitic responses are poorly defined. Here we report a novel immune evasion strategy employed by the parasitoid Exorista sorbillans (Diptera: Tachinidae) to establish infection. We find that E. sorbillans larva construct a respiratory funnel that gradually increases in size as development progresses. This respiratory funnel, which connect to the parasitoid invasion aperture on the host silkworm epidermis, proves essential for E. sorbillans development, as sealing the invasion aperture results in complete mortality of larval parasitoids. Our investigation reveals that E. sorbillans infection reduces both host silkworms' hemocyte counts and the expression of hemocyte-specific genes, while simultaneously inducing varying degrees of host silkworm encapsulation at different parasitic stages. Nevertheless, more complete inhibition of host silkworm encapsulation through RNAi leads to parasitoid's defective respiratory funnel formation and increased mortality rates of the parasitoid. Further observations demonstrate that this suppressed encapsulation response triggers an enhanced activation of Toll/IMD pathways in the host silkworm. Take together, we show that E. sorbillans may utilize host silkworm encapsulation to construct a respiratory funnel for both respiration and immune evasion. Our findings provide new insights into the evasion tactics employed by parasitoids win out in the ongoing parasite-host evolutionary arms race.
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Affiliation(s)
- Qian Xu
- School of Life Sciences, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, 215123, China
| | - Jialei Lu
- School of Life Sciences, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, 215123, China
| | - Xinran Gu
- School of Life Sciences, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, 215123, China
| | - Fupeng Chi
- School of Life Sciences, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, 215123, China
| | - Yue Zhao
- School of Life Sciences, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, 215123, China
| | - Fanchi Li
- School of Life Sciences, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, 215123, China; Sericulture Institute of Soochow University, Suzhou, Jiangsu, 215123, China
| | - Xuejian Jiang
- Guangxi Academy of Forestry Sciences, Nanning, Guangxi, 530002, China.
| | - Bing Li
- School of Life Sciences, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, 215123, China; Sericulture Institute of Soochow University, Suzhou, Jiangsu, 215123, China.
| | - Jing Wei
- School of Life Sciences, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, 215123, China; Sericulture Institute of Soochow University, Suzhou, Jiangsu, 215123, China.
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3
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Nelson KA, Lenhart KF, Anllo L, DiNardo S. The Drosophila hematopoietic niche assembles through collective cell migration controlled by neighbor tissues and Slit-Robo signaling. eLife 2025; 13:RP100455. [PMID: 39750120 PMCID: PMC11698496 DOI: 10.7554/elife.100455] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025] Open
Abstract
Niches are often found in specific positions in tissues relative to the stem cells they support. Consistency of niche position suggests that placement is important for niche function. However, the complexity of most niches has precluded a thorough understanding of how their proper placement is established. To address this, we investigated the formation of a genetically tractable niche, the Drosophila Posterior Signaling Center (PSC), the assembly of which had not been previously explored. This niche controls hematopoietic progenitors of the lymph gland (LG). PSC cells were previously shown to be specified laterally in the embryo, but ultimately reside dorsally, at the LG posterior. Here, using live-imaging, we show that PSC cells migrate as a tight collective and associate with multiple tissues during their trajectory to the LG posterior. We find that Slit emanating from two extrinsic sources, visceral mesoderm and cardioblasts, is required for the PSC to remain a collective, and for its attachment to cardioblasts during migration. Without proper Slit-Robo signaling, PSC cells disperse, form aberrant contacts, and ultimately fail to reach their stereotypical position near progenitors. Our work characterizes a novel example of niche formation and identifies an extrinsic signaling relay that controls precise niche positioning.
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Affiliation(s)
- Kara A Nelson
- Department of Cell and Developmental Biology, Perelman School of Medicine at the University of PennsylvaniaPhiladelphiaUnited States
- Institute for Regenerative Medicine at the University of PennsylvaniaPhiladelphiaUnited States
| | - Kari F Lenhart
- Department of Biology, Drexel UniversityPhiladelphiaUnited States
| | - Lauren Anllo
- Department of Cell and Developmental Biology, Perelman School of Medicine at the University of PennsylvaniaPhiladelphiaUnited States
- Institute for Regenerative Medicine at the University of PennsylvaniaPhiladelphiaUnited States
| | - Stephen DiNardo
- Department of Cell and Developmental Biology, Perelman School of Medicine at the University of PennsylvaniaPhiladelphiaUnited States
- Institute for Regenerative Medicine at the University of PennsylvaniaPhiladelphiaUnited States
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4
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Qin B, Xue H, Wang X, Kim H, Jin LH. Atg2 controls Drosophila hematopoiesis through the PVR/TOR signaling pathways. FEBS J 2025; 292:294-312. [PMID: 39513270 DOI: 10.1111/febs.17288] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2023] [Revised: 06/01/2024] [Accepted: 09/23/2024] [Indexed: 11/15/2024]
Abstract
The hematopoietic system of Drosophila is a well-established genetic model for studying hematopoiesis mechanisms, which are strictly regulated by multiple signaling pathways. Autophagy-related 2 (Atg2) protein is involved in autophagosome formation through its lipid transfer function; however, other functions in animal development, especially the role of Atg2 in maintaining hematopoietic homeostasis, are unclear. Here, we show that Atg2 knockdown in the cortical zone (CZ) induced the proliferation and differentiation of mature plasmatocytes and disrupted progenitor maintenance in the medullary zone (MZ). We also observed the differentiation of lamellocytes among circulating hemocytes and in the lymph gland, which is rarely observed in healthy larvae. The above results on hematopoiesis disorders are due to Atg2 regulating the Drosophila PDGF/VEGF receptor (PVR) and target of rapamycin (TOR) in the CZ of lymph gland. In conclusion, we identified Atg2 as a previously undescribed regulator of hematopoiesis. Understanding the mechanism of maintenance of hematopoietic homeostasis in Drosophila will help us better evaluate human blood disorder-related diseases.
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Affiliation(s)
- Bo Qin
- College of Life Sciences, Northeast Forestry University, Harbin, China
- Institute of Crop Breeding, Heilongjiang Academy of Agricultural Sciences, Harbin, China
| | - Hongmei Xue
- Peking University People's Hospital, Qingdao, China
- Women and Children's Hospital, Qingdao University, China
| | - Xiaoran Wang
- College of Life Sciences, Northeast Forestry University, Harbin, China
| | - Hyonil Kim
- College of Life Sciences, Northeast Forestry University, Harbin, China
- College of Life Science, Kim Il Sung University, Pyongyang, Korea
| | - Li Hua Jin
- College of Life Sciences, Northeast Forestry University, Harbin, China
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5
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Luo F, Sui L, Sun Y, Lai Z, Zhang C, Zhang G, Bi B, Yu S, Jin LH. Rab1 and Syntaxin 17 regulate hematopoietic homeostasis through β-integrin trafficking in Drosophila. J Genet Genomics 2025; 52:51-65. [PMID: 39542172 DOI: 10.1016/j.jgg.2024.11.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Revised: 11/01/2024] [Accepted: 11/05/2024] [Indexed: 11/17/2024]
Abstract
Hematopoiesis is crucial for organismal health, and Drosophila serves as an effective genetic model due to conserved regulatory mechanisms with vertebrates. In larvae, hematopoiesis primarily occurs in the lymph gland, which contains distinct zones, including the cortical zone, intermediate zone, medullary zone, and posterior signaling center (PSC). Rab1 is vital for membrane trafficking and maintaining the localization of cell adhesion molecules, yet its role in hematopoietic homeostasis is not fully understood. This study investigates the effects of Rab1 dysfunction on β-integrin trafficking within circulating hemocytes and lymph gland cells. Rab1 impairment disrupts the endosomal trafficking of β-integrin, leading to its abnormal localization on cell membranes, which promotes lamellocyte differentiation and alters progenitor dynamics in circulating hemocytes and lymph glands, respectively. We also show that the mislocalization of β-integrin is dependent on the adhesion protein DE-cadherin. The reduction of β-integrin at cell boundaries in PSC cells leads to fewer PSC cells and lamellocyte differentiation. Furthermore, Rab1 regulates the trafficking of β-integrin via the Q-SNARE protein Syntaxin 17 (Syx17). Our findings indicate that Rab1 and Syx17 regulate distinct trafficking pathways for β-integrin in different hematopoietic compartments and maintain hematopoietic homeostasis of Drosophila.
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Affiliation(s)
- Fangzhou Luo
- College of Life Sciences, Northeast Forestry University, Harbin, Heilongjiang 150040, China
| | - Luwei Sui
- College of Life Sciences, Northeast Forestry University, Harbin, Heilongjiang 150040, China
| | - Ying Sun
- College of Life Sciences, Northeast Forestry University, Harbin, Heilongjiang 150040, China
| | - Zhixian Lai
- College of Life Sciences, Northeast Forestry University, Harbin, Heilongjiang 150040, China
| | - Chengcheng Zhang
- College of Life Sciences, Northeast Forestry University, Harbin, Heilongjiang 150040, China
| | - Gaoqun Zhang
- Department of Developmental Immunology, Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany
| | - Bing Bi
- College of Life Sciences, Northeast Forestry University, Harbin, Heilongjiang 150040, China
| | - Shichao Yu
- College of Life Sciences, Northeast Forestry University, Harbin, Heilongjiang 150040, China.
| | - Li Hua Jin
- College of Life Sciences, Northeast Forestry University, Harbin, Heilongjiang 150040, China.
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6
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Deichsel S, Frankenreiter L, Fechner J, Gahr BM, Zimmermann M, Mastel H, Preis I, Preiss A, Nagel AC. Inhibition of the Notch signal transducer CSL by Pkc53E-mediated phosphorylation to fend off parasitic immune challenge in Drosophila. eLife 2024; 12:RP89582. [PMID: 39503739 PMCID: PMC11540305 DOI: 10.7554/elife.89582] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2024] Open
Abstract
Notch signalling activity regulates hematopoiesis in Drosophila and vertebrates alike. Parasitoid wasp infestation of Drosophila larvae, however, requires a timely downregulation of Notch activity to allow the formation of encapsulation-active blood cells. Here, we show that the Drosophila CSL transcription factor Suppressor of Hairless [Su(H)] is phosphorylated at Serine 269 in response to parasitoid wasp infestation. As this phosphorylation interferes with the DNA binding of Su(H), it reversibly precludes its activity. Accordingly, phospho-deficient Su(H)S269A mutants are immune-compromised. A screen for kinases involved in Su(H) phosphorylation identified Pkc53E, required for normal hematopoiesis as well as for parasitoid immune response. Genetic and molecular interactions support the specificity of the Su(H)-Pkc53E relationship. Moreover, phorbol ester treatment inhibits Su(H) activity in vivo and in human cell culture. We conclude that Pkc53E targets Su(H) during parasitic wasp infestation, thereby remodelling the blood cell population required for wasp egg encapsulation.
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Affiliation(s)
- Sebastian Deichsel
- Department of Molecular Genetics, Institute of Biology, University of HohenheimStuttgartGermany
- Department of Medical Genetics and Applied Genomics, University of TübingenTübingenGermany
| | - Lisa Frankenreiter
- Department of Molecular Genetics, Institute of Biology, University of HohenheimStuttgartGermany
| | - Johannes Fechner
- Department of Molecular Genetics, Institute of Biology, University of HohenheimStuttgartGermany
- Institute of Biomedical Genetics (IBMG), University of StuttgartStuttgartGermany
| | - Bernd M Gahr
- Department of Molecular Genetics, Institute of Biology, University of HohenheimStuttgartGermany
- Department of Internal Medicine II, Molecular Cardiology, University of UlmUlmGermany
| | - Mirjam Zimmermann
- Department of Molecular Genetics, Institute of Biology, University of HohenheimStuttgartGermany
| | - Helena Mastel
- Department of Molecular Genetics, Institute of Biology, University of HohenheimStuttgartGermany
| | - Irina Preis
- Department of Molecular Genetics, Institute of Biology, University of HohenheimStuttgartGermany
| | - Anette Preiss
- Department of Molecular Genetics, Institute of Biology, University of HohenheimStuttgartGermany
| | - Anja C Nagel
- Department of Molecular Genetics, Institute of Biology, University of HohenheimStuttgartGermany
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7
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Kharrat B, Gábor E, Virág N, Sinka R, Jankovics F, Kristó I, Vilmos P, Csordás G, Honti V. Dual role for Headcase in hemocyte progenitor fate determination in Drosophila melanogaster. PLoS Genet 2024; 20:e1011448. [PMID: 39466810 PMCID: PMC11515969 DOI: 10.1371/journal.pgen.1011448] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Accepted: 10/03/2024] [Indexed: 10/30/2024] Open
Abstract
The hematopoietic organ of the Drosophila larva, the lymph gland, is a simplified representation of mammalian hematopoietic compartments, with the presence of hemocyte progenitors in the medullary zone (MZ), differentiated hemocytes in the cortical zone (CZ), and a hematopoietic niche called the posterior signaling centre (PSC) that orchestrates progenitor differentiation. Our previous work has demonstrated that the imaginal cell factor Headcase (Hdc, Heca) is required in the hematopoietic niche to control the differentiation of hemocyte progenitors. However, the downstream mechanisms of Hdc-mediated hematopoietic control remained unknown. Here we show that Hdc exerts this function by negatively regulating the insulin/mTOR signaling in the niche. When Hdc is depleted in the PSC, the overactivation of this pathway triggers reactive oxygen species (ROS) accumulation and, in turn, the differentiation of effector lamellocytes non-cell-autonomously. Although overactivation of insulin/mTOR signaling normally leads to an increase in the size of the hematopoietic niche, this effect is concealed by cell death caused by hdc loss-of-function. Moreover, we describe here that hdc silencing in progenitors causes cell-autonomous ROS elevation and JNK pathway activation, resulting in decreased MZ size and differentiation of lamellocytes. Similarly to the PSC niche, knocking down hdc in the MZ also leads to caspase activation. Notably, depleting Hdc in the progenitors triggers proliferation, an opposing effect to what is observed in the niche. These findings further our understanding of how progenitor maintenance in the larval lymph gland is controlled autonomously and non-cell-autonomously, and point towards new mechanisms potentially regulating HSC maintenance across vertebrates.
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Affiliation(s)
- Bayan Kharrat
- Drosophila Blood Cell Differentiation Group, Institute of Genetics, HUN-REN Biological Research Centre, Szeged, Hungary
| | - Erika Gábor
- Drosophila Blood Cell Differentiation Group, Institute of Genetics, HUN-REN Biological Research Centre, Szeged, Hungary
| | - Nikolett Virág
- Department of Biology, Faculty of Science and Informatics, University of Szeged, Szeged, Hungary
| | - Rita Sinka
- Department of Genetics, Faculty of Science and Informatics, University of Szeged, Szeged, Hungary
| | - Ferenc Jankovics
- Laboratory of Drosophila Germ Cell Differentiation, Institute of Genetics, HUN-REN Biological Research Centre, Szeged, Hungary
| | - Ildikó Kristó
- Drosophila Nuclear Actin Laboratory, Institute of Genetics, HUN-REN Biological Research Centre, Szeged, Hungary
| | - Péter Vilmos
- Drosophila Nuclear Actin Laboratory, Institute of Genetics, HUN-REN Biological Research Centre, Szeged, Hungary
| | - Gábor Csordás
- Lysosomal Degradation Research Group, Institute of Genetics, HUN-REN Biological Research Centre, Szeged, Hungary
| | - Viktor Honti
- Drosophila Blood Cell Differentiation Group, Institute of Genetics, HUN-REN Biological Research Centre, Szeged, Hungary
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8
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Ramesh P, Tiwari SK, Kaizer M, Jangra D, Ghosh K, Mandal S, Mandal L. The NF-κB Factor Relish maintains blood progenitor homeostasis in the developing Drosophila lymph gland. PLoS Genet 2024; 20:e1011403. [PMID: 39250509 PMCID: PMC11424005 DOI: 10.1371/journal.pgen.1011403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Revised: 09/25/2024] [Accepted: 08/24/2024] [Indexed: 09/11/2024] Open
Abstract
Post-larval hematopoiesis in Drosophila largely depends upon the stockpile of progenitors present in the blood-forming organ/lymph gland of the larvae. During larval stages, the lymph gland progenitors gradually accumulate reactive oxygen species (ROS), which is essential to prime them for differentiation. Studies have shown that ROS triggers the activation of JNK (c-Jun Kinase), which upregulates fatty acid oxidation (FAO) to facilitate progenitor differentiation. Intriguingly, despite having ROS, the entire progenitor pool does not differentiate simultaneously in the late larval stages. Using expression analyses, genetic manipulation and pharmacological approaches, we found that the Drosophila NF-κB transcription factor Relish (Rel) shields the progenitor pool from the metabolic pathway that inducts them into the differentiation program by curtailing the activation of JNK. Although ROS serves as the metabolic signal for progenitor differentiation, the input from ROS is monitored by the developmental signal TAK1, which is regulated by Relish. This developmental circuit ensures that the stockpile of ROS-primed progenitors is not exhausted entirely. Our study sheds light on how, during development, integrating NF-κB-like factors with metabolic pathways seem crucial to regulating cell fate transition during development.
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Affiliation(s)
- Parvathy Ramesh
- Developmental Genetics Laboratory, Indian Institute of Science Education and Research Mohali (IISER Mohali), Punjab, INDIA
| | - Satish Kumar Tiwari
- Developmental Genetics Laboratory, Indian Institute of Science Education and Research Mohali (IISER Mohali), Punjab, INDIA
| | - Md Kaizer
- Developmental Genetics Laboratory, Indian Institute of Science Education and Research Mohali (IISER Mohali), Punjab, INDIA
| | - Deepak Jangra
- Developmental Genetics Laboratory, Indian Institute of Science Education and Research Mohali (IISER Mohali), Punjab, INDIA
| | - Kaustuv Ghosh
- Developmental Genetics Laboratory, Indian Institute of Science Education and Research Mohali (IISER Mohali), Punjab, INDIA
| | - Sudip Mandal
- Molecular Cell and Developmental Biology Laboratory, Department of Biological Sciences, Indian Institute of Science Education and Research Mohali (IISER Mohali), Punjab, INDIA
| | - Lolitika Mandal
- Developmental Genetics Laboratory, Indian Institute of Science Education and Research Mohali (IISER Mohali), Punjab, INDIA
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9
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Cho B, Shin M, Chang E, Son S, Shin I, Shim J. S-nitrosylation-triggered unfolded protein response maintains hematopoietic progenitors in Drosophila. Dev Cell 2024; 59:1075-1090.e6. [PMID: 38521056 DOI: 10.1016/j.devcel.2024.02.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 11/27/2023] [Accepted: 02/29/2024] [Indexed: 03/25/2024]
Abstract
The Drosophila lymph gland houses blood progenitors that give rise to myeloid-like blood cells. Initially, blood progenitors proliferate, but later, they become quiescent to maintain multipotency before differentiation. Despite the identification of various factors involved in multipotency maintenance, the cellular mechanism controlling blood progenitor quiescence remains elusive. Here, we identify the expression of nitric oxide synthase in blood progenitors, generating nitric oxide for post-translational S-nitrosylation of protein cysteine residues. S-nitrosylation activates the Ire1-Xbp1-mediated unfolded protein response, leading to G2 cell-cycle arrest. Specifically, we identify the epidermal growth factor receptor as a target of S-nitrosylation, resulting in its retention within the endoplasmic reticulum and blockade of its receptor function. Overall, our findings highlight developmentally programmed S-nitrosylation as a critical mechanism that induces protein quality control in blood progenitors, maintaining their undifferentiated state by inhibiting cell-cycle progression and rendering them unresponsive to paracrine factors.
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Affiliation(s)
- Bumsik Cho
- Department of Life Science, College of Natural Science, Hanyang University, Seoul 04763, Republic of Korea; Research Institute for Natural Science, Hanyang University, Seoul 04763, Republic of Korea
| | - Mingyu Shin
- Department of Life Science, College of Natural Science, Hanyang University, Seoul 04763, Republic of Korea
| | - Eunji Chang
- Department of Life Science, College of Natural Science, Hanyang University, Seoul 04763, Republic of Korea
| | - Seogho Son
- Department of Life Science, College of Natural Science, Hanyang University, Seoul 04763, Republic of Korea
| | - Incheol Shin
- Department of Life Science, College of Natural Science, Hanyang University, Seoul 04763, Republic of Korea; Research Institute for Natural Science, Hanyang University, Seoul 04763, Republic of Korea; Research Institute for Convergence of Basic Science, Hanyang University, Seoul 04763, Republic of Korea
| | - Jiwon Shim
- Department of Life Science, College of Natural Science, Hanyang University, Seoul 04763, Republic of Korea; Research Institute for Natural Science, Hanyang University, Seoul 04763, Republic of Korea; Research Institute for Convergence of Basic Science, Hanyang University, Seoul 04763, Republic of Korea; Hanyang Institute of Bioscience and Biotechnology, Hanyang University, Seoul 04763, Republic of Korea.
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10
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Sinenko SA. Molecular Mechanisms of Drosophila Hematopoiesis. Acta Naturae 2024; 16:4-21. [PMID: 39188265 PMCID: PMC11345091 DOI: 10.32607/actanaturae.27410] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Accepted: 05/31/2024] [Indexed: 08/28/2024] Open
Abstract
As a model organism, the fruit fly (Drosophila melanogaster) has assumed a leading position in modern biological research. The Drosophila genetic system has a number of advantages making it a key model in investigating the molecular mechanisms of metazoan developmental processes. Over the past two decades, significant progress has been made in understanding the molecular mechanisms regulating Drosophila hematopoiesis. This review discusses the major advances in investigating the molecular mechanisms involved in maintaining the population of multipotent progenitor cells and their differentiation into mature hemocytes in the hematopoietic organ of the Drosophila larva. The use of the Drosophila hematopoietic organ as a model system for hematopoiesis has allowed to characterize the complex interactions between signaling pathways and transcription factors in regulating the maintenance and differentiation of progenitor cells through the signals from the hematopoietic niche, autocrine and paracrine signals, and the signals emanated by differentiated cells.
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Affiliation(s)
- S. A. Sinenko
- Institute of Cytology Russian Academy of Sciences, St. Petersburg, 194064 Russian Federation
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11
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Yang J, Xu Q, Shen W, Jiang Z, Gu X, Li F, Li B, Wei J. The Toll/IMD pathways mediate host protection against dipteran parasitoids. JOURNAL OF INSECT PHYSIOLOGY 2024; 153:104614. [PMID: 38272205 DOI: 10.1016/j.jinsphys.2024.104614] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Revised: 12/30/2023] [Accepted: 01/15/2024] [Indexed: 01/27/2024]
Abstract
Parasitoids have utilized a variety of strategies to counteract host defense. They are in different taxonomic status and exhibit phenotypic and genetic diversity, and thus are thought to evolve distinct anti-defense mechanisms. In this study, we investigated the performance of two closely related parasitoids, Exorista japonica and Exorista sorbillans (Diptera: Tachinidae) that are biological control agents in agriculture and major insect pests in sericulture, on the host Bombyx mori. We show that the host is more susceptible to E. sorbillans infection while relatively resistant to E. japonica infection. Moreover, the expression levels of host antimicrobial peptides (AMPs) genes are repressed at early infection and induced at late infection of E. japonica, while AMPs are over-expressed at early infection and return to normal levels at late infection of E. sorbillans. In parallel, Toll and IMD pathway genes are generally induced at late infection of E. japonica, whereas these genes are up-regulated at early infection and down-regulated at late infection of E. sorbillans. Activating of host Toll/IMD pathways and AMPs expression by lipopolysaccharide (LPS) represses the larval growth of E. sorbillans. Conversely, inhibiting host Toll/IMD pathways by RNA interference significantly promotes E. japonica development. Therefore, the Toll/IMD pathways are required in the host for defense against infection of dipteran parasitoids. Overall, our study provides the new insight into the diversified host-parasitoid interactions, and offers a theoretical basis for further studies of the adaptive mechanism of dipteran parasitoids.
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Affiliation(s)
- Jin Yang
- School of Basic Medicine and Biological Sciences, Soochow University, Suzhou, Jiangsu 215123, China; Sericulture Institute of Soochow University, Suzhou, Jiangsu 215123, China
| | - Qian Xu
- School of Basic Medicine and Biological Sciences, Soochow University, Suzhou, Jiangsu 215123, China
| | - Wenwen Shen
- Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu 215123, China
| | - Zhe Jiang
- School of Basic Medicine and Biological Sciences, Soochow University, Suzhou, Jiangsu 215123, China
| | - Xinran Gu
- School of Basic Medicine and Biological Sciences, Soochow University, Suzhou, Jiangsu 215123, China
| | - Fanchi Li
- School of Basic Medicine and Biological Sciences, Soochow University, Suzhou, Jiangsu 215123, China; Sericulture Institute of Soochow University, Suzhou, Jiangsu 215123, China
| | - Bing Li
- School of Basic Medicine and Biological Sciences, Soochow University, Suzhou, Jiangsu 215123, China; Sericulture Institute of Soochow University, Suzhou, Jiangsu 215123, China.
| | - Jing Wei
- School of Basic Medicine and Biological Sciences, Soochow University, Suzhou, Jiangsu 215123, China; Sericulture Institute of Soochow University, Suzhou, Jiangsu 215123, China; Guangxi Collaborative Innovation Center of Modern Sericulture and Silk, School of Chemistry and Bioengineering, Hechi University, Yizhou, China.
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12
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Mehta D, Chaudhary S, Sunil S. Oxidative stress governs mosquito innate immune signalling to reduce chikungunya virus infection in Aedes-derived cells. J Gen Virol 2024; 105. [PMID: 38488850 DOI: 10.1099/jgv.0.001966] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/19/2024] Open
Abstract
Arboviruses such as chikungunya, dengue and zika viruses cause debilitating diseases in humans. The principal vector species that transmits these viruses is the Aedes mosquito. Lack of substantial knowledge of the vector species hinders the advancement of strategies for controlling the spread of arboviruses. To supplement our information on mosquitoes' responses to virus infection, we utilized Aedes aegypti-derived Aag2 cells to study changes at the transcriptional level during infection with chikungunya virus (CHIKV). We observed that genes belonging to the redox pathway were significantly differentially regulated. Upon quantifying reactive oxygen species (ROS) in the cells during viral infection, we further discovered that ROS levels are considerably higher during the early hours of infection; however, as the infection progresses, an increase in antioxidant gene expression suppresses the oxidative stress in cells. Our study also suggests that ROS is a critical regulator of viral replication in cells and inhibits intracellular and extracellular viral replication by promoting the Rel2-mediated Imd immune signalling pathway. In conclusion, our study provides evidence for a regulatory role of oxidative stress in infected Aedes-derived cells.
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Affiliation(s)
- Divya Mehta
- Vector Borne Diseases Group, International Centre for Genetic Engineering and Biotechnology, New Delhi, India
| | - Sakshi Chaudhary
- Vector Borne Diseases Group, International Centre for Genetic Engineering and Biotechnology, New Delhi, India
| | - Sujatha Sunil
- Vector Borne Diseases Group, International Centre for Genetic Engineering and Biotechnology, New Delhi, India
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13
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Chou J, Ramroop JR, Saravia-Butler AM, Wey B, Lera MP, Torres ML, Heavner ME, Iyer J, Mhatre SD, Bhattacharya S, Govind S. Drosophila parasitoids go to space: Unexpected effects of spaceflight on hosts and their parasitoids. iScience 2024; 27:108759. [PMID: 38261932 PMCID: PMC10797188 DOI: 10.1016/j.isci.2023.108759] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Revised: 10/15/2023] [Accepted: 12/13/2023] [Indexed: 01/25/2024] Open
Abstract
While fruit flies (Drosophila melanogaster) and humans exhibit immune system dysfunction in space, studies examining their immune systems' interactions with natural parasites in space are lacking. Drosophila parasitoid wasps modify blood cell function to suppress host immunity. In this study, naive and parasitized ground and space flies from a tumor-free control and a blood tumor-bearing mutant strain were examined. Inflammation-related genes were activated in space in both fly strains. Whereas control flies did not develop tumors, tumor burden increased in the space-returned tumor-bearing mutants. Surprisingly, control flies were more sensitive to spaceflight than mutant flies; many of their essential genes were downregulated. Parasitoids appeared more resilient than fly hosts, and spaceflight did not significantly impact wasp survival or the expression of their virulence genes. Previously undocumented mutant wasps with novel wing color and wing shape were isolated post-flight and will be invaluable for host-parasite studies on Earth.
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Affiliation(s)
- Jennifer Chou
- Biology Department, The City College of New York, 160 Convent Avenue, New York, NY 10031, USA
| | - Johnny R. Ramroop
- Biology Department, The City College of New York, 160 Convent Avenue, New York, NY 10031, USA
| | - Amanda M. Saravia-Butler
- KBR NASA Ames Research Center, Moffett Field, CA 94035, USA
- Space Biosciences Division, NASA Ames Research Center, Moffett Field, CA 94035, USA
| | - Brian Wey
- Biology Department, The City College of New York, 160 Convent Avenue, New York, NY 10031, USA
- PhD Program in Biology, The Graduate Center of the City University of New York, 365 Fifth Avenue, New York, NY 10016, USA
| | - Matthew P. Lera
- Space Biosciences Division, NASA Ames Research Center, Moffett Field, CA 94035, USA
| | - Medaya L. Torres
- Space Biosciences Division, NASA Ames Research Center, Moffett Field, CA 94035, USA
- Bionetics, NASA Ames Research Center, Moffett Field, CA 94035, USA
| | - Mary Ellen Heavner
- Biology Department, The City College of New York, 160 Convent Avenue, New York, NY 10031, USA
- PhD Program in Biochemistry, The Graduate Center of the City University of New York, 365 Fifth Avenue, New York, NY 10016, USA
| | - Janani Iyer
- KBR NASA Ames Research Center, Moffett Field, CA 94035, USA
- Space Biosciences Division, NASA Ames Research Center, Moffett Field, CA 94035, USA
- Universities Space Research Association, Mountain View, CA 94043, USA
| | - Siddhita D. Mhatre
- KBR NASA Ames Research Center, Moffett Field, CA 94035, USA
- Space Biosciences Division, NASA Ames Research Center, Moffett Field, CA 94035, USA
| | | | - Shubha Govind
- Biology Department, The City College of New York, 160 Convent Avenue, New York, NY 10031, USA
- PhD Program in Biology, The Graduate Center of the City University of New York, 365 Fifth Avenue, New York, NY 10016, USA
- PhD Program in Biochemistry, The Graduate Center of the City University of New York, 365 Fifth Avenue, New York, NY 10016, USA
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14
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Hersperger F, Meyring T, Weber P, Chhatbar C, Monaco G, Dionne MS, Paeschke K, Prinz M, Groß O, Classen AK, Kierdorf K. DNA damage signaling in Drosophila macrophages modulates systemic cytokine levels in response to oxidative stress. eLife 2024; 12:RP86700. [PMID: 38189792 PMCID: PMC10945508 DOI: 10.7554/elife.86700] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2024] Open
Abstract
Environmental factors, infection, or injury can cause oxidative stress in diverse tissues and loss of tissue homeostasis. Effective stress response cascades, conserved from invertebrates to mammals, ensure reestablishment of homeostasis and tissue repair. Hemocytes, the Drosophila blood-like cells, rapidly respond to oxidative stress by immune activation. However, the precise signals how they sense oxidative stress and integrate these signals to modulate and balance the response to oxidative stress in the adult fly are ill-defined. Furthermore, hemocyte diversification was not explored yet on oxidative stress. Here, we employed high-throughput single nuclei RNA-sequencing to explore hemocytes and other cell types, such as fat body, during oxidative stress in the adult fly. We identified distinct cellular responder states in plasmatocytes, the Drosophila macrophages, associated with immune response and metabolic activation upon oxidative stress. We further define oxidative stress-induced DNA damage signaling as a key sensor and a rate-limiting step in immune-activated plasmatocytes controlling JNK-mediated release of the pro-inflammatory cytokine unpaired-3. We subsequently tested the role of this specific immune activated cell stage during oxidative stress and found that inhibition of DNA damage signaling in plasmatocytes, as well as JNK or upd3 overactivation, result in a higher susceptibility to oxidative stress. Our findings uncover that a balanced composition and response of hemocyte subclusters is essential for the survival of adult Drosophila on oxidative stress by regulating systemic cytokine levels and cross-talk to other organs, such as the fat body, to control energy mobilization.
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Affiliation(s)
- Fabian Hersperger
- Institute of Neuropathology, Faculty of Medicine, Medical Center, University of FreiburgFreiburgGermany
- Faculty of Biology, University of FreiburgFreiburgGermany
| | - Tim Meyring
- Institute of Neuropathology, Faculty of Medicine, Medical Center, University of FreiburgFreiburgGermany
| | - Pia Weber
- Institute of Neuropathology, Faculty of Medicine, Medical Center, University of FreiburgFreiburgGermany
| | - Chintan Chhatbar
- Institute of Neuropathology, Faculty of Medicine, Medical Center, University of FreiburgFreiburgGermany
| | - Gianni Monaco
- Institute of Neuropathology, Faculty of Medicine, Medical Center, University of FreiburgFreiburgGermany
- Institute for Transfusion Medicine and Gene Therapy, Medical Center-University of FreiburgFreiburgGermany
| | - Marc S Dionne
- MRC Centre for Molecular Bacteriology and Infection, Imperial College LondonLondonUnited Kingdom
- Department of Life Sciences, Imperial College LondonLondonUnited Kingdom
| | - Katrin Paeschke
- Department of Oncology, Haematology and Rheumatology, University Hospital BonnBonnGermany
- Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital BonnBonnGermany
| | - Marco Prinz
- Institute of Neuropathology, Faculty of Medicine, Medical Center, University of FreiburgFreiburgGermany
- Center for Basics in NeuroModulation (NeuroModulBasics), Faculty of Medicine, University of FreiburgFreiburgGermany
- Signalling Research Centres BIOSS and CIBSS, University of FreiburgFreiburgGermany
| | - Olaf Groß
- Institute of Neuropathology, Faculty of Medicine, Medical Center, University of FreiburgFreiburgGermany
- Center for Basics in NeuroModulation (NeuroModulBasics), Faculty of Medicine, University of FreiburgFreiburgGermany
- Signalling Research Centres BIOSS and CIBSS, University of FreiburgFreiburgGermany
| | - Anne-Kathrin Classen
- Hilde-Mangold-Haus, Faculty of Biology, University of FreiburgFreiburgGermany
- CIBSS-Centre for Integrative Biological Signalling Studies, University of FreiburgFreiburgGermany
| | - Katrin Kierdorf
- Institute of Neuropathology, Faculty of Medicine, Medical Center, University of FreiburgFreiburgGermany
- Center for Basics in NeuroModulation (NeuroModulBasics), Faculty of Medicine, University of FreiburgFreiburgGermany
- CIBSS-Centre for Integrative Biological Signalling Studies, University of FreiburgFreiburgGermany
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15
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Bazzi W, Monticelli S, Delaporte C, Riet C, Giangrande A, Cattenoz PB. Gcm counteracts Toll-induced inflammation and impacts hemocyte number through cholinergic signaling. Front Immunol 2023; 14:1293766. [PMID: 38035083 PMCID: PMC10684909 DOI: 10.3389/fimmu.2023.1293766] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Accepted: 10/26/2023] [Indexed: 12/02/2023] Open
Abstract
Hemocytes, the myeloid-like immune cells of Drosophila, fulfill a variety of functions that are not completely understood, ranging from phagocytosis to transduction of inflammatory signals. We here show that downregulating the hemocyte-specific Glial cell deficient/Glial cell missing (Glide/Gcm) transcription factor enhances the inflammatory response to the constitutive activation of the Toll pathway. This correlates with lower levels of glutathione S-transferase, suggesting an implication of Glide/Gcm in reactive oxygen species (ROS) signaling and calling for a widespread anti-inflammatory potential of Glide/Gcm. In addition, our data reveal the expression of acetylcholine receptors in hemocytes and that Toll activation affects their expressions, disclosing a novel aspect of the inflammatory response mediated by neurotransmitters. Finally, we provide evidence for acetylcholine receptor nicotinic acetylcholine receptor alpha 6 (nAchRalpha6) regulating hemocyte proliferation in a cell autonomous fashion and for non-cell autonomous cholinergic signaling regulating the number of hemocytes. Altogether, this study provides new insights on the molecular pathways involved in the inflammatory response.
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Affiliation(s)
- Wael Bazzi
- Université de Strasbourg, IGBMC UMR 7104- UMR-S 1258, Illkirch, France
- CNRS, UMR 7104, Illkirch, France
- Inserm, UMR-S 1258, Illkirch, France
- IGBMC, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France
| | - Sara Monticelli
- Université de Strasbourg, IGBMC UMR 7104- UMR-S 1258, Illkirch, France
- CNRS, UMR 7104, Illkirch, France
- Inserm, UMR-S 1258, Illkirch, France
- IGBMC, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France
| | - Claude Delaporte
- Université de Strasbourg, IGBMC UMR 7104- UMR-S 1258, Illkirch, France
- CNRS, UMR 7104, Illkirch, France
- Inserm, UMR-S 1258, Illkirch, France
- IGBMC, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France
| | - Céline Riet
- Université de Strasbourg, IGBMC UMR 7104- UMR-S 1258, Illkirch, France
- CNRS, UMR 7104, Illkirch, France
- Inserm, UMR-S 1258, Illkirch, France
- IGBMC, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France
| | - Angela Giangrande
- Université de Strasbourg, IGBMC UMR 7104- UMR-S 1258, Illkirch, France
- CNRS, UMR 7104, Illkirch, France
- Inserm, UMR-S 1258, Illkirch, France
- IGBMC, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France
| | - Pierre B. Cattenoz
- Université de Strasbourg, IGBMC UMR 7104- UMR-S 1258, Illkirch, France
- CNRS, UMR 7104, Illkirch, France
- Inserm, UMR-S 1258, Illkirch, France
- IGBMC, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France
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16
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Zhang W, Wang D, Si J, Jin L, Hao Y. Gbb Regulates Blood Cell Proliferation and Differentiation through JNK and EGFR Signaling Pathways in the Drosophila Lymph Gland. Cells 2023; 12:cells12040661. [PMID: 36831328 PMCID: PMC9954825 DOI: 10.3390/cells12040661] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Revised: 02/08/2023] [Accepted: 02/17/2023] [Indexed: 02/22/2023] Open
Abstract
The Drosophila lymph gland is an ideal model for studying hematopoiesis, and unraveling the mechanisms of Drosophila hematopoiesis can improve our understanding of the pathogenesis of human hematopoietic malignancies. Bone morphogenetic protein (BMP) signaling is involved in a variety of biological processes and is highly conserved between Drosophila and mammals. Decapentaplegic (Dpp)/BMP signaling is known to limit posterior signaling center (PSC) cell proliferation by repressing the protooncogene dmyc. However, the role of two other TGF-β family ligands, Glass bottom boat (Gbb) and Screw (Scw), in Drosophila hematopoiesis is currently largely unknown. Here, we showed that the loss of Gbb in the cortical zone (CZ) induced lamellocyte differentiation by overactivation of the EGFR and JNK pathways and caused excessive differentiation of plasmatocytes, mainly by the hyperactivation of EGFR. Furthermore, we found that Gbb was also required for preventing the hyperproliferation of the lymph glands by inhibiting the overactivation of the Epidermal Growth Factor Receptor (EGFR) and c-Jun N-terminal Kinase (JNK) pathways. These results further advance our understanding of the roles of Gbb protein and the BMP signaling in Drosophila hematopoiesis and the regulatory relationship between the BMP, EGFR, and JNK pathways in the proliferation and differentiation of lymph gland hemocytes.
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Affiliation(s)
- Wenhao Zhang
- Department of Genetics, College of Life Sciences, Northeast Forestry University, Harbin 150040, China
| | - Dongmei Wang
- Department of Basic Medical, Shenyang Medical College, Shenyang 110034, China
| | - Jingjing Si
- Department of Basic Medical, Shenyang Medical College, Shenyang 110034, China
| | - Lihua Jin
- Department of Genetics, College of Life Sciences, Northeast Forestry University, Harbin 150040, China
- Correspondence: (L.J.); (Y.H.)
| | - Yangguang Hao
- Department of Basic Medical, Shenyang Medical College, Shenyang 110034, China
- Correspondence: (L.J.); (Y.H.)
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17
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Arguelles J, Lee J, Cardenas LV, Govind S, Singh S. In Silico Analysis of a Drosophila Parasitoid Venom Peptide Reveals Prevalence of the Cation-Polar-Cation Clip Motif in Knottin Proteins. Pathogens 2023; 12:pathogens12010143. [PMID: 36678491 PMCID: PMC9865768 DOI: 10.3390/pathogens12010143] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 01/10/2023] [Accepted: 01/11/2023] [Indexed: 01/18/2023] Open
Abstract
As generalist parasitoid wasps, Leptopilina heterotoma are highly successful on many species of fruit flies of the genus Drosophila. The parasitoids produce specialized multi-strategy extracellular vesicle (EV)-like structures in their venom. Proteomic analysis identified several immunity-associated proteins, including the knottin peptide, LhKNOT, containing the structurally conserved inhibitor cysteine knot (ICK) fold, which is present in proteins from diverse taxa. Our structural and docking analysis of LhKNOT's 36-residue core knottin fold revealed that in addition to the knottin motif itself, it also possesses a Cation-Polar-Cation (CPC) clip. The CPC clip motif is thought to facilitate antimicrobial activity in heparin-binding proteins. Surprisingly, a majority of ICKs tested also possess the CPC clip motif, including 75 bona fide plant and arthropod knottin proteins that share high sequence and/or structural similarity with LhKNOT. Like LhKNOT and these other 75 knottin proteins, even the Drosophila Drosomycin antifungal peptide, a canonical target gene of the fly's Toll-NF-kappa B immune pathway, contains this CPC clip motif. Together, our results suggest a possible defensive function for the parasitoid LhKNOT. The prevalence of the CPC clip motif, intrinsic to the cysteine knot within the knottin proteins examined here, suggests that the resultant 3D topology is important for their biochemical functions. The CPC clip is likely a highly conserved structural motif found in many diverse proteins with reported heparin binding capacity, including amyloid proteins. Knottins are targets for therapeutic drug development, and insights into their structure-function relationships will advance novel drug design.
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Affiliation(s)
- Joseph Arguelles
- Department of Biology, Brooklyn College, Brooklyn, NY 11210, USA
| | - Jenny Lee
- Department of Biology, Brooklyn College, Brooklyn, NY 11210, USA
| | - Lady V. Cardenas
- Department of Biology, The City College of New York, New York, NY 10031, USA
| | - Shubha Govind
- Department of Biology, The City College of New York, New York, NY 10031, USA
- PhD Program in Biochemistry, The Graduate Center of the City University of New York, New York, NY 10016, USA
- PhD Program in Biology, The Graduate Center of the City University of New York, New York, NY 10016, USA
| | - Shaneen Singh
- Department of Biology, Brooklyn College, Brooklyn, NY 11210, USA
- PhD Program in Biochemistry, The Graduate Center of the City University of New York, New York, NY 10016, USA
- PhD Program in Biology, The Graduate Center of the City University of New York, New York, NY 10016, USA
- Correspondence:
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18
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D'Souza LC, Kuriakose N, Raghu SV, Kabekkodu SP, Sharma A. ROS-directed activation of Toll/NF-κB in the hematopoietic niche triggers benzene-induced emergency hematopoiesis. Free Radic Biol Med 2022; 193:190-201. [PMID: 36216301 DOI: 10.1016/j.freeradbiomed.2022.10.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 09/17/2022] [Accepted: 10/04/2022] [Indexed: 11/19/2022]
Abstract
Hematopoietic stem cells/progenitor cells (HSC/HPCs) orchestrate the hematopoietic process, effectively regulated by the hematopoietic niche under normal and stressed conditions. The hematopoietic niche provides various soluble factors which influence the differentiation and self-renewal of HSC/HSPs. Unceasing differentiation/proliferation/high metabolic activity of HSC/HPCs makes them susceptible to damage by environmental toxicants like benzene. Oxidative stress, epigenetic modifications, and DNA damage in the HSC/HPCs are the key factors of benzene-induced hematopoietic injury. However, the role of the hematopoietic niche in benzene-induced hematopoietic injury/response is still void. Therefore, the current study aims to unravel the role of the hematopoietic niche in benzene-induced hematotoxicity using a genetically tractable model, Drosophila melanogaster. The lymph gland is a dedicated hematopoietic organ in Drosophila larvae. A group of 30-45 cells called the posterior signaling center (PSC) in the lymph gland acts as a niche that regulates Drosophila HSC/HPCs maintenance. Benzene exposure to Drosophila larvae (48 h) resulted in aberrant hemocyte production, especially hyper-differentiation of lamellocytes followed by premature lymph gland dispersal and reduced adult emergence upon developmental exposure. Subsequent genetic experiments revealed that benzene-induced lamellocyte production and premature lymph gland dispersal were PSC mediated. The genetic experiments further showed that benzene generates Dual oxidase (Duox)-dependent Reactive Oxygen Species (ROS) in the PSC, activating Toll/NF-κB signaling, which is essential for the aberrant hemocyte production, lymph gland dispersal, and larval survival. Together, the study establishes a functional perspective of the hematopoietic niche in a benzene-induced hematopoietic emergency in a genetic model, Drosophila, which might be relevant to higher organisms.
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Affiliation(s)
- Leonard Clinton D'Souza
- Nitte (Deemed to be University), Nitte University Centre for Science Education and Research (NUCSER), Division of Environmental Health and Toxicology, Kotekar-Beeri Road, Deralakatte, Mangaluru, 575018, India
| | - Nithin Kuriakose
- Nitte (Deemed to be University), Nitte University Centre for Science Education and Research (NUCSER), Division of Environmental Health and Toxicology, Kotekar-Beeri Road, Deralakatte, Mangaluru, 575018, India; Nitte (Deemed to be University), Nitte University Centre for Science Education and Research (NUCSER), Division of Proteomics and Cancer Biology, Kotekar-Beeri Road, Deralakatte, Mangaluru, 575018, India
| | - Shamprasad Varija Raghu
- Neurogenetics Lab, Department of Applied Zoology, Mangalore University, Mangalagangothri, Konaje, Karnataka, 574199, India
| | - Shama Prasada Kabekkodu
- Department of Cell and Molecular Biology, Manipal School of Life Science, Manipal Academy of Higher Education, Manipal, 576104, India
| | - Anurag Sharma
- Nitte (Deemed to be University), Nitte University Centre for Science Education and Research (NUCSER), Division of Environmental Health and Toxicology, Kotekar-Beeri Road, Deralakatte, Mangaluru, 575018, India.
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19
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Cheng YX, Xu WB, Dong WR, Zhang YM, Li BW, Chen DY, Xiao Y, Guo XL, Shu MA. Identification and functional analysis of epidermal growth factor receptor (EGFR) from Scylla paramamosain: The first evidence of two EGFR genes in animal and their involvement in immune defense against pathogen infection. Mol Immunol 2022; 151:143-157. [PMID: 36150275 DOI: 10.1016/j.molimm.2022.08.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 08/01/2022] [Accepted: 08/04/2022] [Indexed: 12/29/2022]
Abstract
The epidermal growth factor receptor (EGFR) is a pleiotropic glycoprotein which plays a role in regulating cell proliferation, migration and differentiation. However, the genetic diversity of EGFR in crustaceans as well as its function, such as whether it is involved in immune regulation, remains obscure. In this study, two EGFR genes, including EGFR1 and EGFR2, and three transcripts were identified and characterized in Scylla Paramamosain for the first time. To our knowledge, this is the first time that more than one EGFR gene was identified in a single species. The complete open reading frames (ORFs) of SpEGFR1, SpEGFR2a and SpEGFR2b were 4377 bp, 4404 bp and 4341 bp encoding deduced proteins of 1458 amino acids (aa), 1467 aa and 1446 aa, respectively. All EGFR had a signal peptide region and two Recep_L_domain region, followed by a transmembrane region and a conserved tyrosine kinase domain (TyrKc), and phylogenetic analysis demonstrated three SpEGFRs clustered together with invertebrate EGFR branch. Tissue specific expression analysis depicted that all SpEGFRs presented similar transcription patterns. The expression levels of SpEGFR1 and SpEGFR2s in hepatopancreas and gills were significantly altered after the stimulation of bacterial and viral pathogens including Staphylococcus aureus, Vibrio alginolyticus, White spot syndromre virus and Polycytidylinic acid. The in vivo RNA interference assays demonstrated that expression levels of SpIKK, two members of NF-κB (SpRelish and SpDorsal) and six antimicrobial peptide (AMP) genes (SpCrustin and SpALF1-5) were significantly reduced when SpEGFR1 or SpEGFR2 was silenced, respectively. The transcription patterns of SpIKK, SpRelish, SpDorsal and AMPs exhibited similar down- or up-regulation trend when the primary cultured hemocytes were treated with EGFR antagonist or agonist for 24 h. These results suggested that SpEGFR might play an important role in innate immune responses to bacterial and viral infections by regulating the NF-κB pathway. It also provided a better understanding of the origin or evolution of EGFR in crustaceans and even invertebrates.
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Affiliation(s)
- Yuan-Xin Cheng
- College of Animal Sciences, Zhejiang University, Hangzhou 310058, China
| | - Wen-Bin Xu
- College of Animal Sciences, Zhejiang University, Hangzhou 310058, China
| | - Wei-Ren Dong
- College of Animal Sciences, Zhejiang University, Hangzhou 310058, China
| | - Yan-Mei Zhang
- College of Animal Sciences, Zhejiang University, Hangzhou 310058, China
| | - Bing-Wu Li
- College of Animal Sciences, Zhejiang University, Hangzhou 310058, China
| | - Da-Yong Chen
- College of Animal Sciences, Zhejiang University, Hangzhou 310058, China
| | - Yi Xiao
- College of Animal Sciences, Zhejiang University, Hangzhou 310058, China
| | - Xiao-Ling Guo
- College of Animal Sciences, Zhejiang University, Hangzhou 310058, China.
| | - Miao-An Shu
- College of Animal Sciences, Zhejiang University, Hangzhou 310058, China.
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20
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Kinoshita S, Takarada K, Kinoshita Y, Inoue YH. Drosophila hemocytes recognize lymph gland tumors of mxc mutants and activate the innate immune pathway in a reactive oxygen species-dependent manner. Biol Open 2022; 11:bio059523. [PMID: 36226812 PMCID: PMC9641529 DOI: 10.1242/bio.059523] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Accepted: 10/03/2022] [Indexed: 12/29/2022] Open
Abstract
Mechanisms of cancer cell recognition and elimination by the innate immune system remains unclear. The immune signaling pathways are activated in the fat body to suppress the tumor growth in mxcmbn1 hematopoietic tumor mutants in Drosophila by inducing antimicrobial peptides (AMP). Here, we investigated the regulatory mechanism underlying the activation in the mutant. Firstly, we found that reactive oxygen species (ROS) accumulated in the hemocytes due to induction of dual oxidase and one of its activators. This was required for the AMP induction and the tumor growth suppression. Next, more hemocytes transplanted from normal larvae were associated with the mutant tumor than normal lymph glands (LGs). Matrix metalloproteinase 1 and 2 (MMP2) were highly expressed in the tumors. The basement membrane components in the tumors were reduced and ultimately lost inside. Depletion of the MMP2 rather than MMP1 resulted in a significantly reduced AMP expression in the mutant larvae. The hemocytes may recognize the disassembly of basement membrane in the tumors and activate the ROS production. Our findings highlight the mechanism via which macrophage-like hemocytes recognize tumor cells and subsequently convey the information to induce AMPs in the fat body. They contribute to uncover the role of innate immune system against cancer.
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Affiliation(s)
- Suzuko Kinoshita
- Biomedical Research Center, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto, 606-8585, Japan
| | - Kazuki Takarada
- Biomedical Research Center, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto, 606-8585, Japan
| | - Yuriko Kinoshita
- Biomedical Research Center, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto, 606-8585, Japan
| | - Yoshihiro H. Inoue
- Biomedical Research Center, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto, 606-8585, Japan
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21
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Ogienko AA, Omelina ES, Bylino OV, Batin MA, Georgiev PG, Pindyurin AV. Drosophila as a Model Organism to Study Basic Mechanisms of Longevity. Int J Mol Sci 2022; 23:11244. [PMID: 36232546 PMCID: PMC9569508 DOI: 10.3390/ijms231911244] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 09/20/2022] [Accepted: 09/20/2022] [Indexed: 11/16/2022] Open
Abstract
The spatio-temporal regulation of gene expression determines the fate and function of various cells and tissues and, as a consequence, the correct development and functioning of complex organisms. Certain mechanisms of gene activity regulation provide adequate cell responses to changes in environmental factors. Aside from gene expression disorders that lead to various pathologies, alterations of expression of particular genes were shown to significantly decrease or increase the lifespan in a wide range of organisms from yeast to human. Drosophila fruit fly is an ideal model system to explore mechanisms of longevity and aging due to low cost, easy handling and maintenance, large number of progeny per adult, short life cycle and lifespan, relatively low number of paralogous genes, high evolutionary conservation of epigenetic mechanisms and signalling pathways, and availability of a wide range of tools to modulate gene expression in vivo. Here, we focus on the organization of the evolutionarily conserved signaling pathways whose components significantly influence the aging process and on the interconnections of these pathways with gene expression regulation.
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Affiliation(s)
- Anna A. Ogienko
- Department of Regulation of Genetic Processes, Institute of Molecular and Cellular Biology SB RAS, 630090 Novosibirsk, Russia
| | - Evgeniya S. Omelina
- Department of Regulation of Genetic Processes, Institute of Molecular and Cellular Biology SB RAS, 630090 Novosibirsk, Russia
- Laboratory of Biotechnology, Novosibirsk State Agrarian University, 630039 Novosibirsk, Russia
| | - Oleg V. Bylino
- Laboratory of Gene Expression Regulation in Development, Institute of Gene Biology RAS, 119334 Moscow, Russia
| | - Mikhail A. Batin
- Open Longevity, 15260 Ventura Blvd., Sherman Oaks, Los Angeles, CA 91403, USA
| | - Pavel G. Georgiev
- Laboratory of Gene Expression Regulation in Development, Institute of Gene Biology RAS, 119334 Moscow, Russia
| | - Alexey V. Pindyurin
- Department of Regulation of Genetic Processes, Institute of Molecular and Cellular Biology SB RAS, 630090 Novosibirsk, Russia
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22
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Prasad AR, Lago-Baldaia I, Bostock MP, Housseini Z, Fernandes VM. Differentiation signals from glia are fine-tuned to set neuronal numbers during development. eLife 2022; 11:78092. [PMID: 36094172 PMCID: PMC9507125 DOI: 10.7554/elife.78092] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 09/11/2022] [Indexed: 11/13/2022] Open
Abstract
Neural circuit formation and function require that diverse neurons are specified in appropriate numbers. Known strategies for controlling neuronal numbers involve regulating either cell proliferation or survival. We used the Drosophila visual system to probe how neuronal numbers are set. Photoreceptors from the eye-disc induce their target field, the lamina, such that for every unit eye there is a corresponding lamina unit (column). Although each column initially contains ~6 post-mitotic lamina precursors, only 5 differentiate into neurons, called L1-L5; the 'extra' precursor, which is invariantly positioned above the L5 neuron in each column, undergoes apoptosis. Here, we showed that a glial population called the outer chiasm giant glia (xgO), which resides below the lamina, secretes multiple ligands to induce L5 differentiation in response to EGF from photoreceptors. By forcing neuronal differentiation in the lamina, we uncovered that though fated to die, the 'extra' precursor is specified as an L5. Therefore, two precursors are specified as L5s but only one differentiates during normal development. We found that the row of precursors nearest to xgO differentiate into L5s and, in turn, antagonise differentiation signalling to prevent the 'extra' precursors from differentiating, resulting in their death. Thus, an intricate interplay of glial signals and feedback from differentiating neurons defines an invariant and stereotyped pattern of neuronal differentiation and programmed cell death to ensure that lamina columns each contain exactly one L5 neuron.
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Affiliation(s)
- Anadika R Prasad
- Department of Cell and Developmental Biology, University College London, London, United Kingdom
| | - Inês Lago-Baldaia
- Department of Cell and Developmental Biology, University College London, London, United Kingdom
| | - Matthew P Bostock
- Department of Cell and Developmental Biology, University College London, London, United Kingdom
| | - Zaynab Housseini
- Department of Cell and Developmental Biology, University College London, London, United Kingdom
| | - Vilaiwan M Fernandes
- Department of Cell and Developmental Biology, University College London, London, United Kingdom
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23
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Dai M, Yang J, Liu X, Gu H, Li F, Li B, Wei J. Parasitism by the Tachinid Parasitoid Exorista japonica Leads to Suppression of Basal Metabolism and Activation of Immune Response in the Host Bombyx mori. INSECTS 2022; 13:insects13090792. [PMID: 36135493 PMCID: PMC9506100 DOI: 10.3390/insects13090792] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/30/2022] [Revised: 08/26/2022] [Accepted: 08/29/2022] [Indexed: 05/26/2023]
Abstract
The dipteran tachinid parasitoids are important biocontrol agents, and they must survive the harsh environment and rely on the resources of the host insect to complete their larval stage. We have previously demonstrated that the parasitism by the tachinid parasitoid Exoristajaponica, a pest of the silkworm, causes pupation defects in Bombyx mori. However, the underlying mechanism is not fully understood. Here, we performed transcriptome analysis of the fat body of B. mori parasitized by E. japonica. We identified 1361 differentially expressed genes, with 394 genes up-regulated and 967 genes down-regulated. The up-regulated genes were mainly associated with immune response, endocrine system and signal transduction, whereas the genes related to basal metabolism, including energy metabolism, transport and catabolism, lipid metabolism, amino acid metabolism and carbohydrate metabolism were down-regulated, indicating that the host appeared to be in poor nutritional status but active in immune response. Moreover, by time-course gene expression analysis we found that genes related to amino acid synthesis, protein degradation and lipid metabolism in B. mori at later parasitization stages were inhibited. Antimicrobial peptides including Cecropin A, Gloverin and Moricin, and an immulectin, CTL11, were induced. These results indicate that the tachinid parasitoid perturbs the basal metabolism and induces the energetically costly immunity of the host, and thus leading to incomplete larval-pupal ecdysis of the host. This study provided insights into how tachinid parasitoids modify host basal metabolism and immune response for the benefit of developing parasitoid larvae.
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Affiliation(s)
- Minli Dai
- School of Basic Medicine and Biological Sciences, Soochow University, Suzhou 215123, China
| | - Jin Yang
- School of Basic Medicine and Biological Sciences, Soochow University, Suzhou 215123, China
| | - Xinyi Liu
- School of Basic Medicine and Biological Sciences, Soochow University, Suzhou 215123, China
| | - Haoyi Gu
- School of Basic Medicine and Biological Sciences, Soochow University, Suzhou 215123, China
| | - Fanchi Li
- School of Basic Medicine and Biological Sciences, Soochow University, Suzhou 215123, China
- Sericulture Institute, Soochow University, Suzhou 215123, China
| | - Bing Li
- School of Basic Medicine and Biological Sciences, Soochow University, Suzhou 215123, China
- Sericulture Institute, Soochow University, Suzhou 215123, China
| | - Jing Wei
- School of Basic Medicine and Biological Sciences, Soochow University, Suzhou 215123, China
- Sericulture Institute, Soochow University, Suzhou 215123, China
- College of Plant Protection, Fujian Agriculture and Forestry University, Fuzhou 350002, China
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24
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Yu S, Luo F, Xu Y, Zhang Y, Jin LH. Drosophila Innate Immunity Involves Multiple Signaling Pathways and Coordinated Communication Between Different Tissues. Front Immunol 2022; 13:905370. [PMID: 35911716 PMCID: PMC9336466 DOI: 10.3389/fimmu.2022.905370] [Citation(s) in RCA: 59] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2022] [Accepted: 06/15/2022] [Indexed: 11/13/2022] Open
Abstract
The innate immune response provides the first line of defense against invading pathogens, and immune disorders cause a variety of diseases. The fruit fly Drosophila melanogaster employs multiple innate immune reactions to resist infection. First, epithelial tissues function as physical barriers to prevent pathogen invasion. In addition, macrophage-like plasmatocytes eliminate intruders through phagocytosis, and lamellocytes encapsulate large particles, such as wasp eggs, that cannot be phagocytosed. Regarding humoral immune responses, the fat body, equivalent to the mammalian liver, secretes antimicrobial peptides into hemolymph, killing bacteria and fungi. Drosophila has been shown to be a powerful in vivo model for studying the mechanism of innate immunity and host-pathogen interactions because Drosophila and higher organisms share conserved signaling pathways and factors. Moreover, the ease with which Drosophila genetic and physiological characteristics can be manipulated prevents interference by adaptive immunity. In this review, we discuss the signaling pathways activated in Drosophila innate immunity, namely, the Toll, Imd, JNK, JAK/STAT pathways, and other factors, as well as relevant regulatory networks. We also review the mechanisms by which different tissues, including hemocytes, the fat body, the lymph gland, muscles, the gut and the brain coordinate innate immune responses. Furthermore, the latest studies in this field are outlined in this review. In summary, understanding the mechanism underlying innate immunity orchestration in Drosophila will help us better study human innate immunity-related diseases.
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25
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Morin-Poulard I, Destalminil-Letourneau M, Bataillé L, Frendo JL, Lebreton G, Vanzo N, Crozatier M. Identification of Bipotential Blood Cell/Nephrocyte Progenitors in Drosophila: Another Route for Generating Blood Progenitors. Front Cell Dev Biol 2022; 10:834720. [PMID: 35237606 PMCID: PMC8883574 DOI: 10.3389/fcell.2022.834720] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Accepted: 01/24/2022] [Indexed: 11/13/2022] Open
Abstract
The Drosophila lymph gland is the larval hematopoietic organ and is aligned along the anterior part of the cardiovascular system, composed of cardiac cells, that form the cardiac tube and its associated pericardial cells or nephrocytes. By the end of embryogenesis the lymph gland is composed of a single pair of lobes. Two additional pairs of posterior lobes develop during larval development to contribute to the mature lymph gland. In this study we describe the ontogeny of lymph gland posterior lobes during larval development and identify the genetic basis of the process. By lineage tracing we show here that each posterior lobe originates from three embryonic pericardial cells, thus establishing a bivalent blood cell/nephrocyte potential for a subset of embryonic pericardial cells. The posterior lobes of L3 larvae posterior lobes are composed of heterogeneous blood progenitors and their diversity is progressively built during larval development. We further establish that in larvae, homeotic genes and the transcription factor Klf15 regulate the choice between blood cell and nephrocyte fates. Our data underline the sequential production of blood cell progenitors during larval development.
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Affiliation(s)
- Ismaël Morin-Poulard
- Unité de Biologie Moléculaire et Cellulaire et du Développement (MCD), Centre de Biologie Intégrative (CBI), Université de Toulouse UMR 5077/CNRS, Toulouse, France
| | - Manon Destalminil-Letourneau
- Unité de Biologie Moléculaire et Cellulaire et du Développement (MCD), Centre de Biologie Intégrative (CBI), Université de Toulouse UMR 5077/CNRS, Toulouse, France
| | - Laetitia Bataillé
- Unité de Biologie Moléculaire et Cellulaire et du Développement (MCD), Centre de Biologie Intégrative (CBI), Université de Toulouse UMR 5077/CNRS, Toulouse, France.,CNRS, INSERM, IGDR (Institut de Génétique et Développement de Rennes), UMR6290, ERL U1305, Rennes, France
| | - Jean-Louis Frendo
- Unité de Biologie Moléculaire et Cellulaire et du Développement (MCD), Centre de Biologie Intégrative (CBI), Université de Toulouse UMR 5077/CNRS, Toulouse, France.,INSERM U1301, CNRS 5070, Université de Toulouse, Toulouse, France
| | - Gaëlle Lebreton
- Unité de Biologie Moléculaire et Cellulaire et du Développement (MCD), Centre de Biologie Intégrative (CBI), Université de Toulouse UMR 5077/CNRS, Toulouse, France
| | - Nathalie Vanzo
- Unité de Biologie Moléculaire et Cellulaire et du Développement (MCD), Centre de Biologie Intégrative (CBI), Université de Toulouse UMR 5077/CNRS, Toulouse, France
| | - Michèle Crozatier
- Unité de Biologie Moléculaire et Cellulaire et du Développement (MCD), Centre de Biologie Intégrative (CBI), Université de Toulouse UMR 5077/CNRS, Toulouse, France
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26
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Moussalem D, Augé B, Di Stefano L, Osman D, Gobert V, Haenlin M. Two Isoforms of serpent Containing Either One or Two GATA Zinc Fingers Provide Functional Diversity During Drosophila Development. Front Cell Dev Biol 2022; 9:795680. [PMID: 35178397 PMCID: PMC8844375 DOI: 10.3389/fcell.2021.795680] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Accepted: 12/29/2021] [Indexed: 11/13/2022] Open
Abstract
GATA transcription factors play crucial roles in various developmental processes in organisms ranging from flies to humans. In mammals, GATA factors are characterized by the presence of two highly conserved domains, the N-terminal (N-ZnF) and the C-terminal (C-ZnF) zinc fingers. The Drosophila GATA factor Serpent (Srp) is produced in different isoforms that contains either both N-ZnF and C-ZnF (SrpNC) or only the C-ZnF (SrpC). Here, we investigated the functional roles ensured by each of these isoforms during Drosophila development. Using the CRISPR/Cas9 technique, we generated new mutant fly lines deleted for one (ΔsrpNC) or the other (ΔsrpC) encoded isoform, and a third one with a single point mutation in the N-ZnF that alters its interaction with its cofactor, the Drosophila FOG homolog U-shaped (Ush). Analysis of these mutants revealed that the Srp zinc fingers are differentially required for Srp to fulfill its functions. While SrpC is essential for embryo to adult viability, SrpNC, which is the closest conserved isoform to that of vertebrates, is not. However, to ensure its specific functions in larval hematopoiesis and fertility, Srp requires the presence of both N- and C-ZnF (SrpNC) and interaction with its cofactor Ush. Our results also reveal that in vivo the presence of N-ZnF restricts rather than extends the ability of GATA factors to regulate the repertoire of C-ZnF bound target genes.
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Affiliation(s)
- Douaa Moussalem
- Molecular, Cellular and Developmental Biology Department (MCD), Center for Integrative Biology (CBI), University of Toulouse, CNRS, UPS, Toulouse, France
| | - Benoit Augé
- Molecular, Cellular and Developmental Biology Department (MCD), Center for Integrative Biology (CBI), University of Toulouse, CNRS, UPS, Toulouse, France
| | - Luisa Di Stefano
- Molecular, Cellular and Developmental Biology Department (MCD), Center for Integrative Biology (CBI), University of Toulouse, CNRS, UPS, Toulouse, France
| | - Dani Osman
- Faculty of Sciences III, Lebanese University, Tripoli, Lebanon.,Azm Center for Research in Biotechnology and Its Applications, LBA3B, EDST, Lebanese University, Tripoli, Lebanon
| | - Vanessa Gobert
- Molecular, Cellular and Developmental Biology Department (MCD), Center for Integrative Biology (CBI), University of Toulouse, CNRS, UPS, Toulouse, France
| | - Marc Haenlin
- Molecular, Cellular and Developmental Biology Department (MCD), Center for Integrative Biology (CBI), University of Toulouse, CNRS, UPS, Toulouse, France
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27
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Ho KYL, Khadilkar RJ, Carr RL, Tanentzapf G. A gap-junction-mediated, calcium-signaling network controls blood progenitor fate decisions in hematopoiesis. Curr Biol 2021; 31:4697-4712.e6. [PMID: 34480855 DOI: 10.1016/j.cub.2021.08.027] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 05/28/2021] [Accepted: 08/06/2021] [Indexed: 11/24/2022]
Abstract
Stem cell homeostasis requires coordinated fate decisions among stem cells that are often widely distributed within a tissue at varying distances from their stem cell niche. This requires a mechanism to ensure robust fate decisions within a population of stem cells. Here, we show that, in the Drosophila hematopoietic organ, the lymph gland (LG), gap junctions form a network that coordinates fate decisions between blood progenitors. Using live imaging of calcium signaling in intact LGs, we find that blood progenitors are connected through a signaling network. Blocking gap junction function disrupts this network, alters the pattern of encoded calcium signals, and leads to loss of progenitors and precocious blood cell differentiation. Ectopic and uniform activation of the calcium-signaling mediator CaMKII restores progenitor homeostasis when gap junctions are disrupted. Overall, these data show that gap junctions equilibrate cell signals between blood progenitors to coordinate fate decisions and maintain hematopoietic homeostasis.
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Affiliation(s)
- Kevin Y L Ho
- Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
| | - Rohan J Khadilkar
- Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC V6T 1Z3, Canada; Advanced Centre for Treatment, Research and Education in Cancer-Tata Memorial Centre (ACTREC-TMC), Kharghar, Navi Mumbai, Maharashtra 410210, India
| | - Rosalyn L Carr
- Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC V6T 1Z3, Canada; School of Biomedical Engineering, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
| | - Guy Tanentzapf
- Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
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28
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Boulet M, Renaud Y, Lapraz F, Benmimoun B, Vandel L, Waltzer L. Characterization of the Drosophila Adult Hematopoietic System Reveals a Rare Cell Population With Differentiation and Proliferation Potential. Front Cell Dev Biol 2021; 9:739357. [PMID: 34722521 PMCID: PMC8550105 DOI: 10.3389/fcell.2021.739357] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2021] [Accepted: 09/22/2021] [Indexed: 02/06/2023] Open
Abstract
While many studies have described Drosophila embryonic and larval blood cells, the hematopoietic system of the imago remains poorly characterized and conflicting data have been published concerning adult hematopoiesis. Using a combination of blood cell markers, we show that the adult hematopoietic system is essentially composed of a few distinct mature blood cell types. In addition, our transcriptomics results indicate that adult and larval blood cells have both common and specific features and it appears that adult hemocytes reactivate many genes expressed in embryonic blood cells. Interestingly, we identify a small set of blood cells that does not express differentiation markers but rather maintains the expression of the progenitor marker domeMeso. Yet, we show that these cells are derived from the posterior signaling center, a specialized population of cells present in the larval lymph gland, rather than from larval blood cell progenitors, and that their maintenance depends on the EBF transcription factor Collier. Furthermore, while these cells are normally quiescent, we find that some of them can differentiate and proliferate in response to bacterial infection. In sum, our results indicate that adult flies harbor a small population of specialized cells with limited hematopoietic potential and further support the idea that no substantial hematopoiesis takes place during adulthood.
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Affiliation(s)
- Manon Boulet
- Université Clermont Auvergne, Centre National de la Recherche Scientifique, Institut National de la Sante et de la Recherche Medicale, Institut Génétique Reproduction et Développement, Clermont-Ferrand, France
| | - Yoan Renaud
- Université Clermont Auvergne, Centre National de la Recherche Scientifique, Institut National de la Sante et de la Recherche Medicale, Institut Génétique Reproduction et Développement, Clermont-Ferrand, France
| | - François Lapraz
- Centre de Biologie du Développement, Centre de Biologie Intégrative, Université de Toulouse, Centre National de la Recherche Scientifique, Université Paul Sabatier, Toulouse, France
| | - Billel Benmimoun
- Centre de Biologie du Développement, Centre de Biologie Intégrative, Université de Toulouse, Centre National de la Recherche Scientifique, Université Paul Sabatier, Toulouse, France
| | - Laurence Vandel
- Université Clermont Auvergne, Centre National de la Recherche Scientifique, Institut National de la Sante et de la Recherche Medicale, Institut Génétique Reproduction et Développement, Clermont-Ferrand, France
| | - Lucas Waltzer
- Université Clermont Auvergne, Centre National de la Recherche Scientifique, Institut National de la Sante et de la Recherche Medicale, Institut Génétique Reproduction et Développement, Clermont-Ferrand, France.,Centre de Biologie du Développement, Centre de Biologie Intégrative, Université de Toulouse, Centre National de la Recherche Scientifique, Université Paul Sabatier, Toulouse, France
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29
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Girard JR, Goins LM, Vuu DM, Sharpley MS, Spratford CM, Mantri SR, Banerjee U. Paths and pathways that generate cell-type heterogeneity and developmental progression in hematopoiesis. eLife 2021; 10:e67516. [PMID: 34713801 PMCID: PMC8610493 DOI: 10.7554/elife.67516] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2021] [Accepted: 10/22/2021] [Indexed: 12/29/2022] Open
Abstract
Mechanistic studies of Drosophila lymph gland hematopoiesis are limited by the availability of cell-type-specific markers. Using a combination of bulk RNA-Seq of FACS-sorted cells, single-cell RNA-Seq, and genetic dissection, we identify new blood cell subpopulations along a developmental trajectory with multiple paths to mature cell types. This provides functional insights into key developmental processes and signaling pathways. We highlight metabolism as a driver of development, show that graded Pointed expression allows distinct roles in successive developmental steps, and that mature crystal cells specifically express an alternate isoform of Hypoxia-inducible factor (Hif/Sima). Mechanistically, the Musashi-regulated protein Numb facilitates Sima-dependent non-canonical, and inhibits canonical, Notch signaling. Broadly, we find that prior to making a fate choice, a progenitor selects between alternative, biologically relevant, transitory states allowing smooth transitions reflective of combinatorial expressions rather than stepwise binary decisions. Increasingly, this view is gaining support in mammalian hematopoiesis.
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Affiliation(s)
- Juliet R Girard
- Department of Molecular, Cell and Developmental Biology, University of California, Los AngelesLos AngelesUnited States
| | - Lauren M Goins
- Department of Molecular, Cell and Developmental Biology, University of California, Los AngelesLos AngelesUnited States
| | - Dung M Vuu
- Department of Molecular, Cell and Developmental Biology, University of California, Los AngelesLos AngelesUnited States
| | - Mark S Sharpley
- Department of Molecular, Cell and Developmental Biology, University of California, Los AngelesLos AngelesUnited States
| | - Carrie M Spratford
- Department of Molecular, Cell and Developmental Biology, University of California, Los AngelesLos AngelesUnited States
| | - Shreya R Mantri
- Department of Molecular, Cell and Developmental Biology, University of California, Los AngelesLos AngelesUnited States
| | - Utpal Banerjee
- Department of Molecular, Cell and Developmental Biology, University of California, Los AngelesLos AngelesUnited States
- Molecular Biology Institute, University of California, Los AngelesLos AngelesUnited States
- Department of Biological Chemistry, University of California, Los AngelesLos AngelesUnited States
- Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los AngelesLos AngelesUnited States
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30
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Yang L, Qiu LM, Fang Q, Stanley DW, Ye GY. Cellular and humoral immune interactions between Drosophila and its parasitoids. INSECT SCIENCE 2021; 28:1208-1227. [PMID: 32776656 DOI: 10.1111/1744-7917.12863] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/17/2020] [Revised: 07/09/2020] [Accepted: 07/30/2020] [Indexed: 05/26/2023]
Abstract
The immune interactions occurring between parasitoids and their host insects, especially in Drosophila-wasp models, have long been the research focus of insect immunology and parasitology. Parasitoid infestation in Drosophila is counteracted by its multiple natural immune defense systems, which include cellular and humoral immunity. Occurring in the hemocoel, cellular immune responses involve the proliferation, differentiation, migration and spreading of host hemocytes and parasitoid encapsulation by them. Contrastingly, humoral immune responses rely more heavily on melanization and on the Toll, Imd and Jak/Stat immune pathways associated with antimicrobial peptides along with stress factors. On the wasps' side, successful development is achieved by introducing various virulence factors to counteract immune responses of Drosophila. Some or all of these factors manipulate the host's immunity for successful parasitism. Here we review current knowledge of the cellular and humoral immune interactions between Drosophila and its parasitoids, focusing on the defense mechanisms used by Drosophila and the strategies evolved by parasitic wasps to outwit it.
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Affiliation(s)
- Lei Yang
- State Key Laboratory of Rice Biology & Ministry of Agriculture Key Lab of Molecular Biology of Crop Pathogens and Insects, Institute of Insect Sciences, Zhejiang University, Hangzhou, China
| | - Li-Ming Qiu
- State Key Laboratory of Rice Biology & Ministry of Agriculture Key Lab of Molecular Biology of Crop Pathogens and Insects, Institute of Insect Sciences, Zhejiang University, Hangzhou, China
| | - Qi Fang
- State Key Laboratory of Rice Biology & Ministry of Agriculture Key Lab of Molecular Biology of Crop Pathogens and Insects, Institute of Insect Sciences, Zhejiang University, Hangzhou, China
| | - David W Stanley
- USDA Agricultural Research Service, Biological Control of Insects Research Laboratory, Columbia, Missouri, United States
| | - Gong-Yin Ye
- State Key Laboratory of Rice Biology & Ministry of Agriculture Key Lab of Molecular Biology of Crop Pathogens and Insects, Institute of Insect Sciences, Zhejiang University, Hangzhou, China
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31
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Chen J, Fang G, Pang L, Sheng Y, Zhang Q, Zhou Y, Zhou S, Lu Y, Liu Z, Zhang Y, Li G, Shi M, Chen X, Zhan S, Huang J. Neofunctionalization of an ancient domain allows parasites to avoid intraspecific competition by manipulating host behaviour. Nat Commun 2021; 12:5489. [PMID: 34531391 PMCID: PMC8446075 DOI: 10.1038/s41467-021-25727-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Accepted: 08/16/2021] [Indexed: 02/08/2023] Open
Abstract
Intraspecific competition is a major force in mediating population dynamics, fuelling adaptation, and potentially leading to evolutionary diversification. Among the evolutionary arms races between parasites, one of the most fundamental and intriguing behavioural adaptations and counter-adaptations are superparasitism and superparasitism avoidance. However, the underlying mechanisms and ecological contexts of these phenomena remain underexplored. Here, we apply the Drosophila parasite Leptopilina boulardi as a study system and find that this solitary endoparasitic wasp provokes a host escape response for superparasitism avoidance. We combine multi-omics and in vivo functional studies to characterize a small set of RhoGAP domain-containing genes that mediate the parasite's manipulation of host escape behaviour by inducing reactive oxygen species in the host central nervous system. We further uncover an evolutionary scenario in which neofunctionalization and specialization gave rise to the novel role of RhoGAP domain in avoiding superparasitism, with an ancestral origin prior to the divergence between Leptopilina specialist and generalist species. Our study suggests that superparasitism avoidance is adaptive for a parasite and adds to our understanding of how the molecular manipulation of host behaviour has evolved in this system.
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Affiliation(s)
- Jiani Chen
- grid.13402.340000 0004 1759 700XInstitute of Insect Sciences, Ministry of Agriculture Key Lab of Molecular Biology of Crop Pathogens and Insect Pests, College of Agriculture and Biotechnology, Zhejiang University, Hangzhou, China
| | - Gangqi Fang
- grid.9227.e0000000119573309CAS Key Laboratory of Insect Developmental and Evolutionary Biology, CAS Center for Excellence in Molecular Plant Sciences, Chinese Academy of Sciences, Shanghai, China ,grid.410726.60000 0004 1797 8419CAS Center for Excellence in Biotic Interactions, University of Chinese Academy of Sciences, Beijing, China
| | - Lan Pang
- grid.13402.340000 0004 1759 700XInstitute of Insect Sciences, Ministry of Agriculture Key Lab of Molecular Biology of Crop Pathogens and Insect Pests, College of Agriculture and Biotechnology, Zhejiang University, Hangzhou, China
| | - Yifeng Sheng
- grid.13402.340000 0004 1759 700XInstitute of Insect Sciences, Ministry of Agriculture Key Lab of Molecular Biology of Crop Pathogens and Insect Pests, College of Agriculture and Biotechnology, Zhejiang University, Hangzhou, China
| | - Qichao Zhang
- grid.13402.340000 0004 1759 700XInstitute of Insect Sciences, Ministry of Agriculture Key Lab of Molecular Biology of Crop Pathogens and Insect Pests, College of Agriculture and Biotechnology, Zhejiang University, Hangzhou, China
| | - Yuenan Zhou
- grid.13402.340000 0004 1759 700XInstitute of Insect Sciences, Ministry of Agriculture Key Lab of Molecular Biology of Crop Pathogens and Insect Pests, College of Agriculture and Biotechnology, Zhejiang University, Hangzhou, China
| | - Sicong Zhou
- grid.13402.340000 0004 1759 700XInstitute of Insect Sciences, Ministry of Agriculture Key Lab of Molecular Biology of Crop Pathogens and Insect Pests, College of Agriculture and Biotechnology, Zhejiang University, Hangzhou, China
| | - Yueqi Lu
- grid.13402.340000 0004 1759 700XInstitute of Insect Sciences, Ministry of Agriculture Key Lab of Molecular Biology of Crop Pathogens and Insect Pests, College of Agriculture and Biotechnology, Zhejiang University, Hangzhou, China
| | - Zhiguo Liu
- grid.13402.340000 0004 1759 700XInstitute of Insect Sciences, Ministry of Agriculture Key Lab of Molecular Biology of Crop Pathogens and Insect Pests, College of Agriculture and Biotechnology, Zhejiang University, Hangzhou, China ,grid.13402.340000 0004 1759 700XKey Laboratory of Biology of Crop Pathogens and Insects of Zhejiang Province, Zhejiang University, Hangzhou, China
| | - Yixiang Zhang
- grid.9227.e0000000119573309CAS Key Laboratory of Insect Developmental and Evolutionary Biology, CAS Center for Excellence in Molecular Plant Sciences, Chinese Academy of Sciences, Shanghai, China ,grid.410726.60000 0004 1797 8419CAS Center for Excellence in Biotic Interactions, University of Chinese Academy of Sciences, Beijing, China
| | - Guiyun Li
- grid.9227.e0000000119573309CAS Key Laboratory of Insect Developmental and Evolutionary Biology, CAS Center for Excellence in Molecular Plant Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Min Shi
- grid.13402.340000 0004 1759 700XInstitute of Insect Sciences, Ministry of Agriculture Key Lab of Molecular Biology of Crop Pathogens and Insect Pests, College of Agriculture and Biotechnology, Zhejiang University, Hangzhou, China ,grid.13402.340000 0004 1759 700XKey Laboratory of Biology of Crop Pathogens and Insects of Zhejiang Province, Zhejiang University, Hangzhou, China
| | - Xuexin Chen
- grid.13402.340000 0004 1759 700XInstitute of Insect Sciences, Ministry of Agriculture Key Lab of Molecular Biology of Crop Pathogens and Insect Pests, College of Agriculture and Biotechnology, Zhejiang University, Hangzhou, China ,grid.13402.340000 0004 1759 700XKey Laboratory of Biology of Crop Pathogens and Insects of Zhejiang Province, Zhejiang University, Hangzhou, China ,grid.13402.340000 0004 1759 700XState Key Lab of Rice Biology, Zhejiang University, Hangzhou, China
| | - Shuai Zhan
- grid.9227.e0000000119573309CAS Key Laboratory of Insect Developmental and Evolutionary Biology, CAS Center for Excellence in Molecular Plant Sciences, Chinese Academy of Sciences, Shanghai, China ,grid.410726.60000 0004 1797 8419CAS Center for Excellence in Biotic Interactions, University of Chinese Academy of Sciences, Beijing, China
| | - Jianhua Huang
- grid.13402.340000 0004 1759 700XInstitute of Insect Sciences, Ministry of Agriculture Key Lab of Molecular Biology of Crop Pathogens and Insect Pests, College of Agriculture and Biotechnology, Zhejiang University, Hangzhou, China ,grid.13402.340000 0004 1759 700XKey Laboratory of Biology of Crop Pathogens and Insects of Zhejiang Province, Zhejiang University, Hangzhou, China
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Morin-Poulard I, Tian Y, Vanzo N, Crozatier M. Drosophila as a Model to Study Cellular Communication Between the Hematopoietic Niche and Blood Progenitors Under Homeostatic Conditions and in Response to an Immune Stress. Front Immunol 2021; 12:719349. [PMID: 34484226 PMCID: PMC8415499 DOI: 10.3389/fimmu.2021.719349] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Accepted: 07/26/2021] [Indexed: 12/23/2022] Open
Abstract
In adult mammals, blood cells are formed from hematopoietic stem progenitor cells, which are controlled by a complex cellular microenvironment called "niche". Drosophila melanogaster is a powerful model organism to decipher the mechanisms controlling hematopoiesis, due both to its limited number of blood cell lineages and to the conservation of genes and signaling pathways throughout bilaterian evolution. Insect blood cells or hemocytes are similar to the mammalian myeloid lineage that ensures innate immunity functions. Like in vertebrates, two waves of hematopoiesis occur in Drosophila. The first wave takes place during embryogenesis. The second wave occurs at larval stages, where two distinct hematopoietic sites are identified: subcuticular hematopoietic pockets and a specialized hematopoietic organ called the lymph gland. In both sites, hematopoiesis is regulated by distinct niches. In hematopoietic pockets, sensory neurons of the peripheral nervous system provide a microenvironment that promotes embryonic hemocyte expansion and differentiation. In the lymph gland blood cells are produced from hematopoietic progenitors. A small cluster of cells called Posterior Signaling Centre (PSC) and the vascular system, along which the lymph gland develops, act collectively as a niche, under homeostatic conditions, to control the balance between maintenance and differentiation of lymph gland progenitors. In response to an immune stress such as wasp parasitism, lymph gland hematopoiesis is drastically modified and shifts towards emergency hematopoiesis, leading to increased progenitor proliferation and their differentiation into lamellocyte, a specific blood cell type which will neutralize the parasite. The PSC is essential to control this emergency response. In this review, we summarize Drosophila cellular and molecular mechanisms involved in the communication between the niche and hematopoietic progenitors, both under homeostatic and stress conditions. Finally, we discuss similarities between mechanisms by which niches regulate hematopoietic stem/progenitor cells in Drosophila and mammals.
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Affiliation(s)
| | - Yushun Tian
- MCD/UMR5077, Centre de Biologie Intégrative (CBI), Toulouse, France
| | - Nathalie Vanzo
- MCD/UMR5077, Centre de Biologie Intégrative (CBI), Toulouse, France
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Wang J, Mason CJ, Ju X, Xue R, Tong L, Peiffer M, Song Y, Zeng R, Felton GW. Parasitoid Causes Cascading Effects on Plant-Induced Defenses Mediated Through the Gut Bacteria of Host Caterpillars. Front Microbiol 2021; 12:708990. [PMID: 34552570 PMCID: PMC8452159 DOI: 10.3389/fmicb.2021.708990] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Accepted: 08/09/2021] [Indexed: 11/18/2022] Open
Abstract
Koinobiont endoparasitoid wasps whose larvae develop inside a host insect alter several important facets of host physiology, potentially causing cascading effects across multiple trophic levels. For instance, the hijacking of the host immune responses may have effects on how insects interact with host plants and microbial associates. However, the parasitoid regulation of insect-plant-microbiome interactions is still understudied. In this study, we used the fall armyworm (FAW), Spodoptera frugiperda, and the braconid parasitoid Cotesia marginiventris to evaluate impacts of parasitism on the gut microbiome of FAW larvae, and respective maize plant defense responses. The level of reactive oxygen species and the microbial community in larval gut underwent significant changes in response to parasitism, leading to a significant reduction of Enterococcus, while elevating the relative abundance of Pseudomonas. FAW with parasitism had lower glucose oxidase (GOX) activity in salivary glands and triggered lower defense responses in maize plants. These changes corresponded to effects on plants, as Pseudomonas inoculated larvae had lower activity of salivary GOX and triggered lower defense responses in maize plants. Our results demonstrated that parasitism had cascading effects on microbial associates across trophic levels and also highlighted that insect gut bacteria may contribute to complex interrelationships among parasitoids, herbivores, and plants.
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Affiliation(s)
- Jie Wang
- Key Laboratory of Ministry of Education for Genetics, Breeding and Multiple Utilization of Crops, College of Agriculture, Fujian Agriculture and Forestry University, Fuzhou, China
- Department of Entomology, Pennsylvania State University, University Park, PA, United States
- State Key Laboratory of Ecological Pest Control for Fujian and Taiwan Crops, Fujian Agriculture and Forestry University, Fuzhou, China
| | - Charles J. Mason
- Department of Entomology, Pennsylvania State University, University Park, PA, United States
| | - Xueyang Ju
- Key Laboratory of Ministry of Education for Genetics, Breeding and Multiple Utilization of Crops, College of Agriculture, Fujian Agriculture and Forestry University, Fuzhou, China
| | - Rongrong Xue
- Key Laboratory of Ministry of Education for Genetics, Breeding and Multiple Utilization of Crops, College of Agriculture, Fujian Agriculture and Forestry University, Fuzhou, China
| | - Lu Tong
- Key Laboratory of Ministry of Education for Genetics, Breeding and Multiple Utilization of Crops, College of Agriculture, Fujian Agriculture and Forestry University, Fuzhou, China
| | - Michelle Peiffer
- Department of Entomology, Pennsylvania State University, University Park, PA, United States
| | - Yuanyuan Song
- Key Laboratory of Ministry of Education for Genetics, Breeding and Multiple Utilization of Crops, College of Agriculture, Fujian Agriculture and Forestry University, Fuzhou, China
- State Key Laboratory of Ecological Pest Control for Fujian and Taiwan Crops, Fujian Agriculture and Forestry University, Fuzhou, China
| | - Rensen Zeng
- Key Laboratory of Ministry of Education for Genetics, Breeding and Multiple Utilization of Crops, College of Agriculture, Fujian Agriculture and Forestry University, Fuzhou, China
- State Key Laboratory of Ecological Pest Control for Fujian and Taiwan Crops, Fujian Agriculture and Forestry University, Fuzhou, China
| | - Gary W. Felton
- Department of Entomology, Pennsylvania State University, University Park, PA, United States
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Sinenko SA, Starkova TY, Kuzmin AA, Tomilin AN. Physiological Signaling Functions of Reactive Oxygen Species in Stem Cells: From Flies to Man. Front Cell Dev Biol 2021; 9:714370. [PMID: 34422833 PMCID: PMC8377544 DOI: 10.3389/fcell.2021.714370] [Citation(s) in RCA: 127] [Impact Index Per Article: 31.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 07/01/2021] [Indexed: 12/14/2022] Open
Abstract
Reactive oxygen species (ROS), superoxide anion and hydrogen peroxide, are generated as byproducts of oxidative phosphorylation in the mitochondria or via cell signaling-induced NADPH oxidases in the cytosol. In the recent two decades, a plethora of studies established that elevated ROS levels generated by oxidative eustress are crucial physiological mediators of many cellular and developmental processes. In this review, we discuss the mechanisms of ROS generation and regulation, current understanding of ROS functions in the maintenance of adult and embryonic stem cells, as well as in the process of cell reprogramming to a pluripotent state. Recently discovered cell-non-autonomous ROS functions mediated by growth factors are crucial for controlling cell differentiation and cellular immune response in Drosophila. Importantly, many physiological functions of ROS discovered in Drosophila may allow for deciphering and understanding analogous processes in human, which could potentially lead to the development of novel therapeutic approaches in ROS-associated diseases treatment.
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Affiliation(s)
- Sergey A Sinenko
- Institute of Cytology, Russian Academy of Sciences, St. Petersburg, Russia
| | | | - Andrey A Kuzmin
- Institute of Cytology, Russian Academy of Sciences, St. Petersburg, Russia
| | - Alexey N Tomilin
- Institute of Cytology, Russian Academy of Sciences, St. Petersburg, Russia
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Kanwal A, Joshi PV, Mandal S, Mandal L. Ubx-Collier signaling cascade maintains blood progenitors in the posterior lobes of the Drosophila larval lymph gland. PLoS Genet 2021; 17:e1009709. [PMID: 34370733 PMCID: PMC8376192 DOI: 10.1371/journal.pgen.1009709] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 08/19/2021] [Accepted: 07/12/2021] [Indexed: 12/02/2022] Open
Abstract
Drosophila larval hematopoiesis occurs in a specialized multi-lobed organ called the lymph gland. Extensive characterization of the organ has provided mechanistic insights into events related to developmental hematopoiesis. Spanning from the thoracic to the abdominal segment of the larvae, this organ comprises a pair of primary, secondary, and tertiary lobes. Much of our understanding arises from the studies on the primary lobe, while the secondary and tertiary lobes have remained mostly unexplored. Previous studies have inferred that these lobes are composed of progenitors that differentiate during pupation; however, the mechanistic basis of this extended progenitor state remains unclear. This study shows that posterior lobe progenitors are maintained by a local signaling center defined by Ubx and Collier in the tertiary lobe. This Ubx zone in the tertiary lobe shares several markers with the niche of the primary lobe. Ubx domain regulates the homeostasis of the posterior lobe progenitors in normal development and an immune-challenged scenario. Our study establishes the lymph gland as a model to tease out how the progenitors interface with the dual niches within an organ during development and disorders.
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Affiliation(s)
- Aditya Kanwal
- Developmental Genetics Laboratory, Department of Biological Sciences, Indian Institute of Science Education and Research (IISER) Mohali, SAS Nagar, Punjab, India
| | - Pranav Vijay Joshi
- Developmental Genetics Laboratory, Department of Biological Sciences, Indian Institute of Science Education and Research (IISER) Mohali, SAS Nagar, Punjab, India
| | - Sudip Mandal
- Molecular Cell and Developmental Biology Laboratory, Department of Biological Sciences, Indian Institute of Science Education and Research (IISER) Mohali, SAS Nagar, Punjab, India
| | - Lolitika Mandal
- Developmental Genetics Laboratory, Department of Biological Sciences, Indian Institute of Science Education and Research (IISER) Mohali, SAS Nagar, Punjab, India
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Ramesh P, Dey NS, Kanwal A, Mandal S, Mandal L. Relish plays a dynamic role in the niche to modulate Drosophila blood progenitor homeostasis in development and infection. eLife 2021; 10:67158. [PMID: 34292149 PMCID: PMC8363268 DOI: 10.7554/elife.67158] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Accepted: 07/14/2021] [Indexed: 12/12/2022] Open
Abstract
Immune challenges demand the gearing up of basal hematopoiesis to combat infection. Little is known about how during development, this switch is achieved to take care of the insult. Here, we show that the hematopoietic niche of the larval lymph gland of Drosophila senses immune challenge and reacts to it quickly through the nuclear factor-κB (NF-κB), Relish, a component of the immune deficiency (Imd) pathway. During development, Relish is triggered by ecdysone signaling in the hematopoietic niche to maintain the blood progenitors. Loss of Relish causes an alteration in the cytoskeletal architecture of the niche cells in a Jun Kinase-dependent manner, resulting in the trapping of Hh implicated in progenitor maintenance. Notably, during infection, downregulation of Relish in the niche tilts the maintenance program toward precocious differentiation, thereby bolstering the cellular arm of the immune response.
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Affiliation(s)
- Parvathy Ramesh
- Department of Biological Sciences, Indian Institute of Science Education and Research (IISER) Mohali, Knowledge City, India.,Developmental Genetics Laboratory, IISER Mohali, SAS Nagar, Punjab, India
| | - Nidhi Sharma Dey
- Department of Biological Sciences, Indian Institute of Science Education and Research (IISER) Mohali, Knowledge City, India.,Developmental Genetics Laboratory, IISER Mohali, SAS Nagar, Punjab, India
| | - Aditya Kanwal
- Department of Biological Sciences, Indian Institute of Science Education and Research (IISER) Mohali, Knowledge City, India.,Developmental Genetics Laboratory, IISER Mohali, SAS Nagar, Punjab, India
| | - Sudip Mandal
- Department of Biological Sciences, Indian Institute of Science Education and Research (IISER) Mohali, Knowledge City, India.,Molecular Cell and Developmental Biology Laboratory, IISER Mohali, SAS Nagar, Punjab, India
| | - Lolitika Mandal
- Department of Biological Sciences, Indian Institute of Science Education and Research (IISER) Mohali, Knowledge City, India.,Developmental Genetics Laboratory, IISER Mohali, SAS Nagar, Punjab, India
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37
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Wan B, Belghazi M, Lemauf S, Poirié M, Gatti JL. Proteomics of purified lamellocytes from Drosophila melanogaster HopT um-l identifies new membrane proteins and networks involved in their functions. INSECT BIOCHEMISTRY AND MOLECULAR BIOLOGY 2021; 134:103584. [PMID: 34033897 DOI: 10.1016/j.ibmb.2021.103584] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 04/20/2021] [Accepted: 04/22/2021] [Indexed: 06/12/2023]
Abstract
In healthy Drosophila melanogaster larvae, plasmatocytes and crystal cells account for 95% and 5% of the hemocytes, respectively. A third type of hemocytes, lamellocytes, are rare, but their number increases after oviposition by parasitoid wasps. The lamellocytes form successive layers around the parasitoid egg, leading to its encapsulation and melanization, and finally the death of this intruder. However, the total number of lamellocytes per larva remains quite low even after parasitoid infestation, making direct biochemical studies difficult. Here, we used the HopTum-l mutant strain that constitutively produces large numbers of lamellocytes to set up a purification method and analyzed their major proteins by 2D gel electrophoresis and their plasma membrane surface proteins by 1D SDS-PAGE after affinity purification. Mass spectrometry identified 430 proteins from 2D spots and 344 affinity-purified proteins from 1D bands, for a total of 639 unique proteins. Known lamellocyte markers such as PPO3 and the myospheroid integrin were among the components identified with specific chaperone proteins. Affinity purification detected other integrins, as well as a wide range of integrin-associated proteins involved in the formation and function of cell-cell junctions. Overall, the newly identified proteins indicate that these cells are highly adapted to the encapsulation process (recognition, motility, adhesion, signaling), but may also have several other physiological functions (such as secretion and internalization of vesicles) under different signaling pathways. These results provide the basis for further in vivo and in vitro studies of lamellocytes, including the development of new markers to identify coexisting populations and their respective origins and functions in Drosophila immunity.
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Affiliation(s)
- Bin Wan
- Université Côte d'Azur, INRAE, CNRS, Institute Sophia-Agrobiotech, Sophia Antipolis, France
| | - Maya Belghazi
- Institute of NeuroPhysiopathology (INP), UMR7051, CNRS, Aix-Marseille Université, Marseille, 13015, France
| | - Séverine Lemauf
- Université Côte d'Azur, INRAE, CNRS, Institute Sophia-Agrobiotech, Sophia Antipolis, France
| | - Marylène Poirié
- Université Côte d'Azur, INRAE, CNRS, Institute Sophia-Agrobiotech, Sophia Antipolis, France
| | - Jean-Luc Gatti
- Université Côte d'Azur, INRAE, CNRS, Institute Sophia-Agrobiotech, Sophia Antipolis, France.
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38
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Streptozotocin activates inflammation-associated signalling and antioxidant response in the lobster cockroach; Nauphoeta cinerea (Blattodea: Blaberidae). Chem Biol Interact 2021; 345:109563. [PMID: 34166651 DOI: 10.1016/j.cbi.2021.109563] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2020] [Revised: 05/17/2021] [Accepted: 06/17/2021] [Indexed: 11/22/2022]
Abstract
Streptozotocin exhibits tropism to insulin-producing beta-cells in mammals and has been used to model diabetes-like phenotypes in insects. We have previously shown increased brain glucose levels and oxidative stress in STZ-treated nymphs of Nauphoeta cinerea. Here, we validate Nauphoeta cinerea as an experimental organism for studying STZ-induced metabolic disruptions by investigating the potential changes in the expression of inflammation and antioxidant related genes. Cockroaches were injected with 0.8% NaCl, 74 and 740 nmol of STZ. mRNA extracted from the head of cockroaches was used to estimate the RT-qPCR expression of inflammation and antioxidant genes. STZ-treatment upregulated the target genes of the JNK pathway (early growth factor response factor and reaper) but had no effect on PDGF-and VEGF-related factor 1. TOLL 1, the target gene of TOLL/NF-kB pathway was up regulated, while both the activator and target gene of the UPD3/JAK/STAT pathway [unpaired 3 and Suppressor of cytokine signalling at 36E] were upregulated. mRNA levels of primary antioxidants (superoxide dismutase and catalase) were increased in STZ treated nymphs but there was no effect on thioredoxins and Peroxiredoxin 4. Likewise, STZ treatment did not affect the expression of the delta class of the glutathione S-transferase gene family, but the sigma and theta classes of the GST family were upregulated. The STZ-induced N. cinerea gene expression modification demonstrates the involvement of primary antioxidants and the GST detoxification system in the cockroach oxidative stress response and buttresses the proposed crosstalk between inflammatory and redox pathways.
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39
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Reactive Oxygen Species-Dependent Innate Immune Mechanisms Control Methicillin-Resistant Staphylococcus aureus Virulence in the Drosophila Larval Model. mBio 2021; 12:e0027621. [PMID: 34126772 PMCID: PMC8262968 DOI: 10.1128/mbio.00276-21] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Antibiotic-resistant Staphylococcus aureus strains constitute a major public health concern worldwide and are responsible for both health care- and community-associated infections. Here, we establish a robust and easy-to-implement model of oral S. aureus infection using Drosophila melanogaster larvae that allowed us to follow the fate of S. aureus at the whole-organism level as well as the host immune responses. Our study demonstrates that S. aureus infection triggers H2O2 production by the host via the Duox enzyme, thereby promoting antimicrobial peptide production through activation of the Toll pathway. Staphylococcal catalase mediates H2O2 neutralization, which not only promotes S. aureus survival but also minimizes the host antimicrobial response, hence reducing bacterial clearance in vivo. We show that while catalase expression is regulated in vitro by the accessory gene regulatory system (Agr) and the general stress response regulator sigma B (SigB), it no longer depends on these two master regulators in vivo. Finally, we confirm the versatility of this model by demonstrating the colonization and host stimulation capabilities of S. aureus strains belonging to different sequence types (CC8 and CC5) as well as of two other bacterial pathogens, Salmonella enterica serovar Typhimurium and Shigella flexneri. Thus, the Drosophila larva can be a general model to follow in vivo the innate host immune responses triggered during infection by human pathogens.
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40
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A parasitoid wasp of Drosophila employs preemptive and reactive strategies to deplete its host's blood cells. PLoS Pathog 2021; 17:e1009615. [PMID: 34048506 PMCID: PMC8191917 DOI: 10.1371/journal.ppat.1009615] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2021] [Revised: 06/10/2021] [Accepted: 05/05/2021] [Indexed: 11/19/2022] Open
Abstract
The wasps Leptopilina heterotoma parasitize and ingest their Drosophila hosts. They produce extracellular vesicles (EVs) in the venom that are packed with proteins, some of which perform immune suppressive functions. EV interactions with blood cells of host larvae are linked to hematopoietic depletion, immune suppression, and parasite success. But how EVs disperse within the host, enter and kill hematopoietic cells is not well understood. Using an antibody marker for L. heterotoma EVs, we show that these parasite-derived structures are readily distributed within the hosts’ hemolymphatic system. EVs converge around the tightly clustered cells of the posterior signaling center (PSC) of the larval lymph gland, a small hematopoietic organ in Drosophila. The PSC serves as a source of developmental signals in naïve animals. In wasp-infected animals, the PSC directs the differentiation of lymph gland progenitors into lamellocytes. These lamellocytes are needed to encapsulate the wasp egg and block parasite development. We found that L. heterotoma infection disassembles the PSC and PSC cells disperse into the disintegrating lymph gland lobes. Genetically manipulated PSC-less lymph glands remain non-responsive and largely intact in the face of L. heterotoma infection. We also show that the larval lymph gland progenitors use the endocytic machinery to internalize EVs. Once inside, L. heterotoma EVs damage the Rab7- and LAMP-positive late endocytic and phagolysosomal compartments. Rab5 maintains hematopoietic and immune quiescence as Rab5 knockdown results in hematopoietic over-proliferation and ectopic lamellocyte differentiation. Thus, both aspects of anti-parasite immunity, i.e., (a) phagocytosis of the wasp’s immune-suppressive EVs, and (b) progenitor differentiation for wasp egg encapsulation reside in the lymph gland. These results help explain why the lymph gland is specifically and precisely targeted for destruction. The parasite’s simultaneous and multipronged approach to block cellular immunity not only eliminates blood cells, but also tactically blocks the genetic programming needed for supplementary hematopoietic differentiation necessary for host success. In addition to its known functions in hematopoiesis, our results highlight a previously unrecognized phagocytic role of the lymph gland in cellular immunity. EV-mediated virulence strategies described for L. heterotoma are likely to be shared by other parasitoid wasps; their understanding can improve the design and development of novel therapeutics and biopesticides as well as help protect biodiversity. Parasitoid wasps serve as biological control agents of agricultural insect pests and are worthy of study. Many parasitic wasps develop inside their hosts to emerge as free-living adults. To overcome the resistance of their hosts, parasitic wasps use varied and ingenious strategies such as mimicry, evasion, bioactive venom, virus-like particles, viruses, and extracellular vesicles (EVs). We describe the effects of a unique class of EVs containing virulence proteins and produced in the venom of wasps that parasitize fruit flies of Drosophila species. EVs from Leptopilina heterotoma are widely distributed throughout the Drosophila hosts’ circulatory system after infection. They enter and kill macrophages by destroying the very same subcellular machinery that facilitates their uptake. An important protein in this process, Rab5, is needed to maintain the identity of the macrophage; when Rab5 function is reduced, macrophages turn into a different cell type called lamellocytes. Activities in the EVs can eliminate lamellocytes as well. EVs also interfere with the hosts’ genetic program that promotes lamellocyte differentiation needed to block parasite development. Thus, wasps combine specific preemptive and reactive strategies to deplete their hosts of the very cells that would otherwise sequester and kill them. These findings have applied value in agricultural pest control and medical therapeutics.
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41
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Rodrigues D, Renaud Y, VijayRaghavan K, Waltzer L, Inamdar MS. Differential activation of JAK-STAT signaling reveals functional compartmentalization in Drosophila blood progenitors. eLife 2021; 10:61409. [PMID: 33594977 PMCID: PMC7920551 DOI: 10.7554/elife.61409] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Accepted: 02/16/2021] [Indexed: 12/17/2022] Open
Abstract
Blood cells arise from diverse pools of stem and progenitor cells. Understanding progenitor heterogeneity is a major challenge. The Drosophila larval lymph gland is a well-studied model to understand blood progenitor maintenance and recapitulates several aspects of vertebrate hematopoiesis. However in-depth analysis has focused on the anterior lobe progenitors (AP), ignoring the posterior progenitors (PP) from the posterior lobes. Using in situ expression mapping and developmental and transcriptome analysis, we reveal PP heterogeneity and identify molecular-genetic tools to study this abundant progenitor population. Functional analysis shows that PP resist differentiation upon immune challenge, in a JAK-STAT-dependent manner. Upon wasp parasitism, AP downregulate JAK-STAT signaling and form lamellocytes. In contrast, we show that PP activate STAT92E and remain undifferentiated, promoting survival. Stat92E knockdown or genetically reducing JAK-STAT signaling permits PP lamellocyte differentiation. We discuss how heterogeneity and compartmentalization allow functional segregation in response to systemic cues and could be widely applicable.
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Affiliation(s)
- Diana Rodrigues
- Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, India.,National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bangalore, India.,Shanmugha Arts, Science, Technology & Research Academy, Tamil Nadu, India
| | - Yoan Renaud
- University of Clermont Auvergne, CNRS, Inserm, GReD, Clermont-Ferrand, France
| | - K VijayRaghavan
- National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bangalore, India.,Shanmugha Arts, Science, Technology & Research Academy, Tamil Nadu, India
| | - Lucas Waltzer
- University of Clermont Auvergne, CNRS, Inserm, GReD, Clermont-Ferrand, France
| | - Maneesha S Inamdar
- Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, India
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Yu S, Luo F, Jin LH. Rab5 and Rab11 maintain hematopoietic homeostasis by restricting multiple signaling pathways in Drosophila. eLife 2021; 10:60870. [PMID: 33560224 PMCID: PMC7891935 DOI: 10.7554/elife.60870] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Accepted: 02/08/2021] [Indexed: 12/26/2022] Open
Abstract
The hematopoietic system of Drosophila is a powerful genetic model for studying hematopoiesis, and vesicle trafficking is important for signal transduction during various developmental processes; however, its interaction with hematopoiesis is currently largely unknown. In this article, we selected three endosome markers, Rab5, Rab7, and Rab11, that play a key role in membrane trafficking and determined whether they participate in hematopoiesis. Inhibiting Rab5 or Rab11 in hemocytes or the cortical zone (CZ) significantly induced cell overproliferation and lamellocyte formation in circulating hemocytes and lymph glands and disrupted blood cell progenitor maintenance. Lamellocyte formation involves the JNK, Toll, and Ras/EGFR signaling pathways. Notably, lamellocyte formation was also associated with JNK-dependent autophagy. In conclusion, we identified Rab5 and Rab11 as novel regulators of hematopoiesis, and our results advance the understanding of the mechanisms underlying the maintenance of hematopoietic homeostasis as well as the pathology of blood disorders such as leukemia.
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Affiliation(s)
- Shichao Yu
- Department of Genetics, College of Life Sciences, Northeast Forestry University, Harbin, China
| | - Fangzhou Luo
- Department of Genetics, College of Life Sciences, Northeast Forestry University, Harbin, China
| | - Li Hua Jin
- Department of Genetics, College of Life Sciences, Northeast Forestry University, Harbin, China
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43
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Destalminil-Letourneau M, Morin-Poulard I, Tian Y, Vanzo N, Crozatier M. The vascular niche controls Drosophila hematopoiesis via fibroblast growth factor signaling. eLife 2021; 10:64672. [PMID: 33395389 PMCID: PMC7781598 DOI: 10.7554/elife.64672] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Accepted: 12/16/2020] [Indexed: 12/22/2022] Open
Abstract
In adult mammals, hematopoiesis, the production of blood cells from hematopoietic stem and progenitor cells (HSPCs), is tightly regulated by extrinsic signals from the microenvironment called 'niche'. Bone marrow HSPCs are heterogeneous and controlled by both endosteal and vascular niches. The Drosophila hematopoietic lymph gland is located along the cardiac tube which corresponds to the vascular system. In the lymph gland, the niche called Posterior Signaling Center controls only a subset of the heterogeneous hematopoietic progenitor population indicating that additional signals are necessary. Here we report that the vascular system acts as a second niche to control lymph gland homeostasis. The FGF ligand Branchless produced by vascular cells activates the FGF pathway in hematopoietic progenitors. By regulating intracellular calcium levels, FGF signaling maintains progenitor pools and prevents blood cell differentiation. This study reveals that two niches contribute to the control ofDrosophila blood cell homeostasis through their differential regulation of progenitors.
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Affiliation(s)
- Manon Destalminil-Letourneau
- Centre de Biologie du Développement (CBD), Centre de Biologie Intégrative (CBI), Université de Toulouse, CNRS, UPS, Toulouse, France
| | - Ismaël Morin-Poulard
- Centre de Biologie du Développement (CBD), Centre de Biologie Intégrative (CBI), Université de Toulouse, CNRS, UPS, Toulouse, France
| | - Yushun Tian
- Centre de Biologie du Développement (CBD), Centre de Biologie Intégrative (CBI), Université de Toulouse, CNRS, UPS, Toulouse, France
| | - Nathalie Vanzo
- Centre de Biologie du Développement (CBD), Centre de Biologie Intégrative (CBI), Université de Toulouse, CNRS, UPS, Toulouse, France
| | - Michele Crozatier
- Centre de Biologie du Développement (CBD), Centre de Biologie Intégrative (CBI), Université de Toulouse, CNRS, UPS, Toulouse, France
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44
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Madhwal S, Shin M, Kapoor A, Goyal M, Joshi MK, Ur Rehman PM, Gor K, Shim J, Mukherjee T. Metabolic control of cellular immune-competency by odors in Drosophila. eLife 2020; 9:60376. [PMID: 33372660 PMCID: PMC7808736 DOI: 10.7554/elife.60376] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Accepted: 12/28/2020] [Indexed: 12/16/2022] Open
Abstract
Studies in different animal model systems have revealed the impact of odors on immune cells; however, any understanding on why and how odors control cellular immunity remained unclear. We find that Drosophila employ an olfactory-immune cross-talk to tune a specific cell type, the lamellocytes, from hematopoietic-progenitor cells. We show that neuronally released GABA derived upon olfactory stimulation is utilized by blood-progenitor cells as a metabolite and through its catabolism, these cells stabilize Sima/HIFα protein. Sima capacitates blood-progenitor cells with the ability to initiate lamellocyte differentiation. This systemic axis becomes relevant for larvae dwelling in wasp-infested environments where chances of infection are high. By co-opting the olfactory route, the preconditioned animals elevate their systemic GABA levels leading to the upregulation of blood-progenitor cell Sima expression. This elevates their immune-potential and primes them to respond rapidly when infected with parasitic wasps. The present work highlights the importance of the olfaction in immunity and shows how odor detection during animal development is utilized to establish a long-range axis in the control of blood-progenitor competency and immune-priming.
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Affiliation(s)
- Sukanya Madhwal
- Institute for Stem Cell Science and Regenerative Medicine (inStem), Bangalore, India.,Manipal Academy of Higher Education, Manipal, India
| | - Mingyu Shin
- Department of Life Science, College of Natural Science, Hanyang University, Seoul, Republic of Korea
| | - Ankita Kapoor
- Institute for Stem Cell Science and Regenerative Medicine (inStem), Bangalore, India.,Manipal Academy of Higher Education, Manipal, India
| | - Manisha Goyal
- Institute for Stem Cell Science and Regenerative Medicine (inStem), Bangalore, India.,The University of Trans-Disciplinary Health Sciences & Technology (TDU), Bengaluru, India
| | - Manish K Joshi
- Institute for Stem Cell Science and Regenerative Medicine (inStem), Bangalore, India
| | | | - Kavan Gor
- Institute for Stem Cell Science and Regenerative Medicine (inStem), Bangalore, India
| | - Jiwon Shim
- Department of Life Science, College of Natural Science, Hanyang University, Seoul, Republic of Korea.,Research Institute for Natural Science, Hanyang University, Seoul, Republic of Korea
| | - Tina Mukherjee
- Institute for Stem Cell Science and Regenerative Medicine (inStem), Bangalore, India
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45
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Leitão AB, Arunkumar R, Day JP, Geldman EM, Morin-Poulard I, Crozatier M, Jiggins FM. Constitutive activation of cellular immunity underlies the evolution of resistance to infection in Drosophila. eLife 2020; 9:59095. [PMID: 33357377 PMCID: PMC7785293 DOI: 10.7554/elife.59095] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Accepted: 12/23/2020] [Indexed: 12/21/2022] Open
Abstract
Organisms rely on inducible and constitutive immune defences to combat infection. Constitutive immunity enables a rapid response to infection but may carry a cost for uninfected individuals, leading to the prediction that it will be favoured when infection rates are high. When we exposed populations of Drosophila melanogaster to intense parasitism by the parasitoid wasp Leptopilina boulardi, they evolved resistance by developing a more reactive cellular immune response. Using single-cell RNA sequencing, we found that immune-inducible genes had become constitutively upregulated. This was the result of resistant larvae differentiating precursors of specialized immune cells called lamellocytes that were previously only produced after infection. Therefore, populations evolved resistance by genetically hard-wiring the first steps of an induced immune response to become constitutive.
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Affiliation(s)
- Alexandre B Leitão
- Department of Genetics, University of Cambridge, Cambridge, United Kingdom
| | - Ramesh Arunkumar
- Department of Genetics, University of Cambridge, Cambridge, United Kingdom
| | - Jonathan P Day
- Department of Genetics, University of Cambridge, Cambridge, United Kingdom
| | - Emma M Geldman
- Department of Genetics, University of Cambridge, Cambridge, United Kingdom
| | - Ismaël Morin-Poulard
- Centre de Biologie du Développement, Centre de Biologie Intégrative, University Paul Sabatier, Toulouse, France
| | - Michèle Crozatier
- Centre de Biologie du Développement, Centre de Biologie Intégrative, University Paul Sabatier, Toulouse, France
| | - Francis M Jiggins
- Department of Genetics, University of Cambridge, Cambridge, United Kingdom
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46
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Peng D, Li J, Deng Y, Zhu X, Zhao L, Zhang Y, Li Z, Ou S, Li S, Jiang Y. Sodium para-aminosalicylic acid inhibits manganese-induced NLRP3 inflammasome-dependent pyroptosis by inhibiting NF-κB pathway activation and oxidative stress. J Neuroinflammation 2020; 17:343. [PMID: 33203418 PMCID: PMC7670624 DOI: 10.1186/s12974-020-02018-6] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Accepted: 10/29/2020] [Indexed: 12/11/2022] Open
Abstract
Background The activation of NOD-like receptor protein 3 (NLRP3) inflammasome-dependent pyroptosis has been shown to play a vital role in the pathology of manganese (Mn)-induced neurotoxicity. Sodium para-aminosalicylic acid (PAS-Na) has a positive effect on the treatment of manganism. However, the mechanism is still unclear. We hypothesized that PAS-Na might act through NLRP3. Methods The microglial cell line BV2 and male Sprague-Dawley rats were used to investigate the impacts of PAS-Na on Mn-induced NLRP3 inflammasome-dependent pyroptosis. The related protein of the NF-κB pathway and NLRP3-inflammasome-dependent pyroptosis was detected by western blot. The reactive oxygen species and mitochondrial membrane potential were detected by immunofluorescence staining and flow cytometry. The activation of microglia and the gasdermin D (GSDMD) were detected by immunofluorescence staining. Results Our results showed that Mn treatment induced oxidative stress and activated the NF-κB pathway by increasing the phosphorylation of p65 and IkB-α in BV2 cells and in the basal ganglia of rats. PAS-Na could alleviate Mn-induced oxidative stress damage by inhibiting ROS generation, increasing mitochondrial membrane potential and ATP levels, thereby reducing the phosphorylation of p65 and IkB-α. Besides, Mn treatment could activate the NLRP3 pathway and promote the secretion of IL-18 and IL-1β, mediating pyroptosis in BV2 cells and in the basal ganglia and hippocampus of rats. But an inhibitor of NF-κb (JSH-23) treatment could significantly reduce LDH release, the expression of NLRP3 and Cleaved CASP1 protein and IL-1β and IL-18 mRNA level in BV2 cells. Interestingly, the effect of PAS-Na treatment in Mn-treated BV2 cells is similar to those of JSH-23. Besides, immunofluorescence results showed that PAS-Na reduced the increase number of activated microglia, which stained positively for GSDMD. Conclusion PAS-Na antagonized Mn-induced NLRP3 inflammasome dependent pyroptosis through inhibiting NF-κB pathway activation and oxidative stress. Supplementary Information The online version contains supplementary material available at 10.1186/s12974-020-02018-6.
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Affiliation(s)
- Dongjie Peng
- Department of Toxicology, School of Public Health, Guangxi Medical University, Shuang-yong Road No.22, Nanning, 530021, Guangxi, China.,Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Shuang-yong Road No.22, Nanning, 530021, Guangxi, China
| | - Junyan Li
- Department of Toxicology, School of Public Health, Guangxi Medical University, Shuang-yong Road No.22, Nanning, 530021, Guangxi, China.,Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Shuang-yong Road No.22, Nanning, 530021, Guangxi, China
| | - Yue Deng
- Department of Toxicology, School of Public Health, Guangxi Medical University, Shuang-yong Road No.22, Nanning, 530021, Guangxi, China.,Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Shuang-yong Road No.22, Nanning, 530021, Guangxi, China
| | - Xiaojuan Zhu
- Department of Toxicology, School of Public Health, Guangxi Medical University, Shuang-yong Road No.22, Nanning, 530021, Guangxi, China.,Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Shuang-yong Road No.22, Nanning, 530021, Guangxi, China
| | - Lin Zhao
- Department of Toxicology, School of Public Health, Guangxi Medical University, Shuang-yong Road No.22, Nanning, 530021, Guangxi, China.,Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Shuang-yong Road No.22, Nanning, 530021, Guangxi, China
| | - Yuwen Zhang
- Department of Toxicology, School of Public Health, Guangxi Medical University, Shuang-yong Road No.22, Nanning, 530021, Guangxi, China.,Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Shuang-yong Road No.22, Nanning, 530021, Guangxi, China
| | - Zhaocong Li
- Department of Toxicology, School of Public Health, Guangxi Medical University, Shuang-yong Road No.22, Nanning, 530021, Guangxi, China.,Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Shuang-yong Road No.22, Nanning, 530021, Guangxi, China
| | - Shiyan Ou
- Department of Toxicology, School of Public Health, Guangxi Medical University, Shuang-yong Road No.22, Nanning, 530021, Guangxi, China.,Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Shuang-yong Road No.22, Nanning, 530021, Guangxi, China
| | - Shaojun Li
- Department of Toxicology, School of Public Health, Guangxi Medical University, Shuang-yong Road No.22, Nanning, 530021, Guangxi, China. .,Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Shuang-yong Road No.22, Nanning, 530021, Guangxi, China.
| | - Yueming Jiang
- Department of Toxicology, School of Public Health, Guangxi Medical University, Shuang-yong Road No.22, Nanning, 530021, Guangxi, China. .,Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Shuang-yong Road No.22, Nanning, 530021, Guangxi, China.
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47
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Chakrabarti S, Visweswariah SS. Intramacrophage ROS Primes the Innate Immune System via JAK/STAT and Toll Activation. Cell Rep 2020; 33:108368. [PMID: 33176146 PMCID: PMC7662148 DOI: 10.1016/j.celrep.2020.108368] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Revised: 12/10/2019] [Accepted: 10/20/2020] [Indexed: 12/27/2022] Open
Abstract
Tissue injury is one of the most severe environmental perturbations for a living organism. When damage occurs in adult Drosophila, there is a local response of the injured tissue and a coordinated action across different tissues to help the organism overcome the deleterious effect of an injury. We show a change in the transcriptome of hemocytes at the site of tissue injury, with pronounced activation of the Toll signaling pathway. We find that induction of the cytokine upd-3 and Toll receptor activation occur in response to injury alone, in the absence of a pathogen. Intracellular accumulation of hydrogen peroxide in hemocytes is essential for upd-3 induction and is facilitated by the diffusion of hydrogen peroxide through a channel protein Prip. Importantly, hemocyte activation and production of reactive oxygen species (ROS) at the site of a sterile injury provide protection to flies on subsequent infection, demonstrating training of the innate immune system.
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Affiliation(s)
- Sveta Chakrabarti
- Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bengaluru, India.
| | - Sandhya S Visweswariah
- Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bengaluru, India
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48
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Lan W, Liu S, Zhao L, Su Y. Regulation of Drosophila Hematopoiesis in Lymph Gland: From a Developmental Signaling Point of View. Int J Mol Sci 2020; 21:ijms21155246. [PMID: 32722007 PMCID: PMC7432643 DOI: 10.3390/ijms21155246] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Revised: 07/22/2020] [Accepted: 07/22/2020] [Indexed: 12/15/2022] Open
Abstract
The Drosophila hematopoietic system is becoming increasingly attractive for its simple blood cell lineage and its developmental and functional parallels with the vertebrate system. As the dedicated organ for Drosophila larval hematopoiesis, the lymph gland harbors both multipotent stem-like progenitor cells and differentiated blood cells. The balance between progenitor maintenance and differentiation in the lymph gland must be precisely and tightly controlled. Multiple developmental signaling pathways, such as Notch, Hedgehog, and Wnt/Wingless, have been demonstrated to regulate the hematopoietic processes in the lymph gland. Focusing on blood cell maintenance and differentiation, this article summarizes the functions of several classic developmental signaling pathways for lymph gland growth and patterning, highlighting the important roles of developmental signaling during lymph gland development as well as Drosophila larval hematopoiesis.
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Affiliation(s)
- Wenwen Lan
- Institute of Evolution & Marine Biodiversity, Ocean University of China, Qingdao 266003, China; (W.L.); (S.L.)
- College of Marine Life Sciences, Ocean University of China, Qingdao 266003, China
| | - Sumin Liu
- Institute of Evolution & Marine Biodiversity, Ocean University of China, Qingdao 266003, China; (W.L.); (S.L.)
- College of Marine Life Sciences, Ocean University of China, Qingdao 266003, China
| | - Long Zhao
- Institute of Evolution & Marine Biodiversity, Ocean University of China, Qingdao 266003, China; (W.L.); (S.L.)
- Fisheries College, Ocean University of China, Qingdao 266003, China
- Correspondence: (L.Z.); (Y.S.)
| | - Ying Su
- Institute of Evolution & Marine Biodiversity, Ocean University of China, Qingdao 266003, China; (W.L.); (S.L.)
- College of Marine Life Sciences, Ocean University of China, Qingdao 266003, China
- Correspondence: (L.Z.); (Y.S.)
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49
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Khadilkar RJ, Ho KYL, Venkatesh B, Tanentzapf G. Integrins Modulate Extracellular Matrix Organization to Control Cell Signaling during Hematopoiesis. Curr Biol 2020; 30:3316-3329.e5. [PMID: 32649911 DOI: 10.1016/j.cub.2020.06.027] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2019] [Revised: 05/04/2020] [Accepted: 06/08/2020] [Indexed: 11/25/2022]
Abstract
During hematopoiesis, progenitor cells receive and interpret a diverse array of regulatory signals from their environment. These signals control the maintenance of the progenitors and regulate the production of mature blood cells. Integrins are well known in vertebrates for their roles in hematopoiesis, particularly in assisting in the migration to, as well as the physical attachment of, progenitors to the niche. However, whether and how integrins are also involved in the signaling mechanisms that control hematopoiesis remains to be resolved. Here, we show that integrins play a key role during fly hematopoiesis in regulating cell signals that control the behavior of hematopoietic progenitors. Integrins can regulate hematopoiesis directly, via focal adhesion kinase (FAK) signaling, and indirectly, by directing extracellular matrix (ECM) assembly and/or maintenance. ECM organization and density controls blood progenitor behavior by modulating multiple signaling pathways, including bone morphogenetic protein (BMP) and Hedgehog (Hh). Furthermore, we show that integrins and the ECM are reduced following infection, which may assist in activating the immune response. Our results provide mechanistic insight into how integrins can shape the signaling environment around hematopoietic progenitors.
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Affiliation(s)
- Rohan J Khadilkar
- Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
| | - Kevin Y L Ho
- Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
| | - Bhavya Venkatesh
- Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
| | - Guy Tanentzapf
- Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
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50
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Luo F, Yu S, Jin LH. The Posterior Signaling Center Is an Important Microenvironment for Homeostasis of the Drosophila Lymph Gland. Front Cell Dev Biol 2020; 8:382. [PMID: 32509789 PMCID: PMC7253591 DOI: 10.3389/fcell.2020.00382] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Accepted: 04/28/2020] [Indexed: 01/02/2023] Open
Abstract
Hematopoiesis is a necessary process for development and immune defense in Drosophila from the embryonic period to adulthood. There are two main stages in this process: the first stage occurs in the head mesoderm during the embryonic stage, and the second occurs in a specialized hematopoietic organ along the dorsal vessel, the lymph gland, during the larval stage. The lymph gland consists of paired lobes, each of which has distinct regions: the cortical zone (CZ), which contains mature hemocytes; the medullary zone (MZ), which contains hematopoietic progenitors; and the posterior signaling center (PSC), which specifically expresses the early B-cell factor (EBF) transcription factor Collier (Col) and the HOX factor Antennapedia (Antp) to form a microenvironment similar to that of the mammalian bone marrow hematopoietic stem cell niche. The PSC plays a key role in regulating hematopoietic progenitor differentiation. Moreover, the PSC contributes to the cellular immune response to wasp parasitism triggered by elevated ROS levels. Two recent studies have revealed that hematopoietic progenitor maintenance is directly regulated by Col expressed in the MZ and is independent of the PSC, challenging the traditional model. In this review, we summarize the regulatory networks of PSC cell proliferation, the controversy regarding PSC-mediated regulation of hematopoietic progenitor differentiation, and the wasp egg infection response. In addition, we discuss why the PSC is an ideal model for investigating mammalian hematopoietic stem cell niches and leukemia.
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Affiliation(s)
| | | | - Li Hua Jin
- Department of Genetics, College of Life Sciences, Northeast Forestry University, Harbin, China
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