|
1
|
Saade M, Martí E. Early spinal cord development: from neural tube formation to neurogenesis. Nat Rev Neurosci 2025; 26:195-213. [PMID: 39915695 DOI: 10.1038/s41583-025-00906-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/20/2025] [Indexed: 03/26/2025]
Abstract
As one of the simplest and most evolutionarily conserved parts of the vertebrate nervous system, the spinal cord serves as a key model for understanding the principles of nervous system construction. During embryonic development, the spinal cord originates from a population of bipotent stem cells termed neuromesodermal progenitors, which are organized within a transient embryonic structure known as the neural tube. Neural tube morphogenesis differs along its anterior-to-posterior axis: most of the neural tube (including the regions that will develop into the brain and the anterior spinal cord) forms via the bending and dorsal fusion of the neural groove, but the establishment of the posterior region of the neural tube involves de novo formation of a lumen within a solid medullary cord. The early spinal cord primordium consists of highly polarized neural progenitor cells organized into a pseudostratified epithelium. Tight regulation of the cell division modes of these progenitors drives the embryonic growth of the neural tube and initiates primary neurogenesis. A rich history of observational and functional studies across various vertebrate models has advanced our understanding of the cellular events underlying spinal cord development, and these foundational studies are beginning to inform our knowledge of human spinal cord development.
Collapse
Affiliation(s)
- Murielle Saade
- Department of Cells and Tissues, Instituto de Biología Molecular de Barcelona CSIC, Barcelona, Spain.
| | - Elisa Martí
- Department of Cells and Tissues, Instituto de Biología Molecular de Barcelona CSIC, Barcelona, Spain.
| |
Collapse
|
|
2
|
Wolf AK, Adams-Phillips LC, Adams AND, Erives AJ, Phillips BT. Nuclear localization and transactivation of SYS-1/β-catenin is the result of serial gene duplications and subfunctionalizations. Cells Dev 2025:204013. [PMID: 40010690 DOI: 10.1016/j.cdev.2025.204013] [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: 11/04/2024] [Revised: 02/04/2025] [Accepted: 02/22/2025] [Indexed: 02/28/2025]
Abstract
β-catenin is a highly conserved multifunctional protein capable of mediating cell adhesion via E-cadherin and transactivation of target genes of the canonical Wnt signaling pathway. The nematode, C. elegans contains four paralogs of β-catenin which are highly specific in their functions. Though similar in overall structure, the four beta-catenins are functionally distinct, each regulating different aspects of development. Of the four, SYS-1 is a key player in Wnt dependent asymmetric cell division (ACD). In ACD, a polarized mother will give rise to a daughter with high nuclear SYS-1 and another with low nuclear SYS-1. Despite sequence dissimilarity, SYS-1 shares a close structural resemblance with human β-catenin where it retains an unstructured amino-terminus (NTD) and 12 armadillo repeats. Using existing genome sequence data from several nematode species, we find that the four β-catenin paralogs result from 3 sequential gene duplications and neofunctionalizations during nematode evolution. SYS-1, however, lacks an unstructured carboxyl-terminus (CTD) that is essential for human β-catenin transactivation processes. This work supports the hypothesis that SYS-1 compensated for the lack of CTD by acquiring novel transactivation domains with cryptic nuclear localization signals in the NTD and the first four armadillo repeats, as shown by transactivation assays in worms and yeast. Furthermore, SYS-1 regulatory domains are not localized to the NTD as in canonical β-catenin and instead spans the entire length of the protein. Truncating SYS-1 abolishes the classical SYS-1 nuclear asymmetry, resulting in daughter cells with symmetrical SYS-1 truncation localization. A screen for SYS-1 physical interactors followed by in vivo SYS-1 localization analyses and effects on cell fate suggest that proper SYS-1 nuclear export is facilitated by XPO-1, while an interaction with IMB-3, an importin β-like protein, suggests import mechanisms. Interestingly, XPO-1 is especially required for lowering SYS-1 in the Wnt-unsignaled nucleus, suggesting a distinct mechanism for regulating asymmetric nuclear SYS-1. In summary, we provide insights on the mechanism of β-catenin evolution within nematodes and inform SYS-1 transactivation and nuclear transport mechanisms.
Collapse
|
|
3
|
Barandun N, Meier B, Stehli G, Gräbnitz F, Zangger N, Oxenius A. Targeted localization of the mother centrosome in CD8 + T cells undergoing asymmetric cell division promotes memory formation. Cell Rep 2025; 44:115127. [PMID: 39764850 DOI: 10.1016/j.celrep.2024.115127] [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: 01/09/2024] [Revised: 07/24/2024] [Accepted: 12/10/2024] [Indexed: 02/01/2025] Open
Abstract
How a single, naive T cell can give rise to diverse progenies of effector and memory cells is not completely understood. One way to achieve this is by asymmetric cell division (ACD), characterized by an unequal distribution of cellular cargo, resulting in divergent daughter cells already after the first division-one being more destined to an effector and the other more to a memory fate. Here, we established two methods to analyze the relative distribution of the older "mother" centrosome and the younger "daughter" centrosome during the first cell division of activated CD8+ T cells. We show that upon ACD, the mother centrosome is inherited by the effector-like daughter cell in a ninein-dependent mechanism. Ninein deletion abolished this effect and led to impaired differentiation of memory-like daughter cells. These findings suggest that directed centrosome inheritance upon ACD has functional effects on the fate diversification of CD8+ T cells.
Collapse
Affiliation(s)
- Niculò Barandun
- Institute of Microbiology, ETH Zürich, Vladimir-Prelog-Weg 4, 8093 Zürich, Switzerland
| | - Benjamin Meier
- Institute of Microbiology, ETH Zürich, Vladimir-Prelog-Weg 4, 8093 Zürich, Switzerland
| | - Gautier Stehli
- Institute of Microbiology, ETH Zürich, Vladimir-Prelog-Weg 4, 8093 Zürich, Switzerland
| | - Fabienne Gräbnitz
- Institute of Microbiology, ETH Zürich, Vladimir-Prelog-Weg 4, 8093 Zürich, Switzerland
| | - Nathan Zangger
- Institute of Microbiology, ETH Zürich, Vladimir-Prelog-Weg 4, 8093 Zürich, Switzerland
| | - Annette Oxenius
- Institute of Microbiology, ETH Zürich, Vladimir-Prelog-Weg 4, 8093 Zürich, Switzerland.
| |
Collapse
|
|
4
|
Bolkent S. Cellular and molecular mechanisms of asymmetric stem cell division in tissue homeostasis. Genes Cells 2024; 29:1099-1110. [PMID: 39379096 PMCID: PMC11609605 DOI: 10.1111/gtc.13172] [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: 02/15/2024] [Revised: 09/09/2024] [Accepted: 09/25/2024] [Indexed: 10/10/2024]
Abstract
The asymmetric cell division determines cell diversity and distinct sibling cell fates by mechanisms linked to mitosis. Many adult stem cells divide asymmetrically to balance self-renewal and differentiation. The process of asymmetric cell division involves an axis of polarity and, second, the localization of cell fate determinants at the cell poles. Asymmetric division of stem cells is achieved by intrinsic and extrinsic fate determinants such as signaling molecules, epigenetics factors, molecules regulating gene expression, and polarized organelles. At least some stem cells perform asymmetric and symmetric cell divisions during development. Asymmetric division ensures that the number of stem cells remains constant throughout life. The asymmetric division of stem cells plays an important role in biological events such as embryogenesis, tissue regeneration and carcinogenesis. This review summarizes recent advances in the regulation of asymmetric stem cell division in model organisms.
Collapse
Affiliation(s)
- Sema Bolkent
- Cerrahpaşa Faculty of Medicine, Department of Medical BiologyIstanbul University‐CerrahpaşaCerrahpaşaIstanbulTurkey
| |
Collapse
|
|
5
|
Arseni C, Samiotaki M, Panayotou G, Simos G, Mylonis I. Combinatorial regulation by ERK1/2 and CK1δ protein kinases leads to HIF-1α association with microtubules and facilitates its symmetrical distribution during mitosis. Cell Mol Life Sci 2024; 81:72. [PMID: 38300329 PMCID: PMC10834586 DOI: 10.1007/s00018-024-05120-7] [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: 10/30/2023] [Revised: 12/13/2023] [Accepted: 01/07/2024] [Indexed: 02/02/2024]
Abstract
Hypoxia-inducible factor-1 (HIF-1) is the key transcriptional mediator of the cellular response to hypoxia and is also involved in cancer progression. Regulation of its oxygen-sensitive HIF-1α subunit involves post-translational modifications that control its stability, subcellular localization, and activity. We have previously reported that phosphorylation of the HIF-1α C-terminal domain by ERK1/2 promotes HIF-1α nuclear accumulation and stimulates HIF-1 activity while lack of this modification triggers HIF-1α nuclear export and its association with mitochondria. On the other hand, modification of the N-terminal domain of HIF-1α by CK1δ impairs HIF-1 activity by obstructing the formation of a HIF-1α/ARNT heterodimer. Investigation of these two antagonistic events by expressing double phospho-site mutants in HIF1A-/- cells under hypoxia revealed independent and additive phosphorylation effects that can create a gradient of HIF-1α subcellular localization and transcriptional activity. Furthermore, modification by CK1δ caused mitochondrial release of the non-nuclear HIF-1α form and binding to microtubules via its N-terminal domain. In agreement, endogenous HIF-1α could be shown to co-localize with mitotic spindle microtubules and interact with tubulin, both of which were inhibited by CK1δ silencing or inhibition. Moreover, CK1δ expression was necessary for equal partitioning of mother cell-produced HIF-1α to the daughter cell nuclei at the end of mitosis. Overall, our results suggest that phosphorylation by CK1δ stimulates the association of non-nuclear HIF-1α with microtubules, which may serve as a means to establish a symmetric distribution of HIF-1α during cell division under low oxygen conditions.
Collapse
Affiliation(s)
- Christina Arseni
- Laboratory of Biochemistry, Faculty of Medicine, University of Thessaly, 41500, Larissa, Greece
| | - Martina Samiotaki
- Institute for Bio-Innovation, BSRC "Alexander Fleming", 16672, Vari, Greece
| | - George Panayotou
- Institute for Bio-Innovation, BSRC "Alexander Fleming", 16672, Vari, Greece
| | - George Simos
- Laboratory of Biochemistry, Faculty of Medicine, University of Thessaly, 41500, Larissa, Greece.
- Gerald Bronfman Department of Oncology, Faculty of Medicine, McGill University, Montreal, Canada.
| | - Ilias Mylonis
- Laboratory of Biochemistry, Faculty of Medicine, University of Thessaly, 41500, Larissa, Greece.
| |
Collapse
|
|
6
|
Langner E, Cheng T, Kefaloyianni E, Gluck C, Wang B, Mahjoub MR. Cep120 is essential for kidney stromal progenitor cell growth and differentiation. EMBO Rep 2024; 25:428-454. [PMID: 38177914 PMCID: PMC10897188 DOI: 10.1038/s44319-023-00019-z] [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: 07/07/2023] [Revised: 11/15/2023] [Accepted: 11/22/2023] [Indexed: 01/06/2024] Open
Abstract
Mutations in genes that disrupt centrosome structure or function can cause congenital kidney developmental defects and lead to fibrocystic pathologies. Yet, it is unclear how defective centrosome biogenesis impacts renal progenitor cell physiology. Here, we examined the consequences of impaired centrosome duplication on kidney stromal progenitor cell growth, differentiation, and fate. Conditional deletion of the ciliopathy gene Cep120, which is essential for centrosome duplication, in the stromal mesenchyme resulted in reduced abundance of interstitial lineages including pericytes, fibroblasts and mesangial cells. These phenotypes were caused by a combination of delayed mitosis, activation of the mitotic surveillance pathway leading to apoptosis, and changes in both Wnt and Hedgehog signaling that are key for differentiation of stromal cells. Cep120 ablation resulted in small hypoplastic kidneys with medullary atrophy and delayed nephron maturation. Finally, Cep120 and centrosome loss in the interstitium sensitized kidneys of adult mice, causing rapid fibrosis after renal injury via enhanced TGF-β/Smad3-Gli2 signaling. Our study defines the cellular and developmental defects caused by loss of Cep120 and aberrant centrosome biogenesis in the embryonic kidney stroma.
Collapse
Affiliation(s)
- Ewa Langner
- Department of Medicine (Nephrology Division), Washington University, St Louis, MO, USA
| | - Tao Cheng
- Department of Medicine (Nephrology Division), Washington University, St Louis, MO, USA
| | - Eirini Kefaloyianni
- Department of Medicine (Rheumatology Division), Washington University, St Louis, MO, USA
| | - Charles Gluck
- Department of Medicine (Nephrology Division), Washington University, St Louis, MO, USA
| | - Baolin Wang
- Department of Genetic Medicine, Weill Medical College of Cornell University, New York, NY, USA
| | - Moe R Mahjoub
- Department of Medicine (Nephrology Division), Washington University, St Louis, MO, USA.
- Department of Cell Biology and Physiology, Washington University, St Louis, MO, USA.
| |
Collapse
|
|
7
|
Gräbnitz F, Oxenius A. CD8 T-cell diversification: Asymmetric cell division and its functional implications. Eur J Immunol 2023; 53:e2250225. [PMID: 36788705 DOI: 10.1002/eji.202250225] [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: 11/11/2022] [Revised: 02/10/2023] [Accepted: 02/10/2023] [Indexed: 02/16/2023]
Abstract
Establishment of cellular diversity is a basic requirement for the development of multicellular organisms. Cellular diversification can be induced by asymmetric cell division (ACD), during which the emerging two daughter cells unequally inherit lineage specific cargo (including transcription factors, receptors for specific signaling inputs, metabolic platforms, and possibly different epigenetic landscapes), resulting in two daughter cells endowed with different fates. While ACD is strongly involved in lineage choices in mammalian stem cells, its role in fate diversification in lineage committed cell subsets that still exhibit plastic potential, such as T-cells, is currently investigated. In this review, we focus predominantly on the role of ACD in fate diversification of CD8 T-cells. Further, we discuss the impact of differential T-cell receptor stimulation strengths and differentiation history on ACD-mediated fate diversification and highlight a particular importance of ACD in the development of memory CD8 T-cells upon high-affinity stimulation conditions.
Collapse
Affiliation(s)
- Fabienne Gräbnitz
- Institute of Microbiology, ETH Zurich, Vladimir-Prelog-Weg 4, Zurich, 8093, Switzerland
| | - Annette Oxenius
- Institute of Microbiology, ETH Zurich, Vladimir-Prelog-Weg 4, Zurich, 8093, Switzerland
| |
Collapse
|
|
8
|
Langner E, Cheng T, Kefaloyianni E, Gluck C, Wang B, Mahjoub MR. Impaired centrosome biogenesis in kidney stromal progenitors reduces abundance of interstitial lineages and accelerates injury-induced fibrosis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.04.04.535583. [PMID: 37066241 PMCID: PMC10104024 DOI: 10.1101/2023.04.04.535583] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/18/2023]
Abstract
Defective centrosome function can disrupt embryonic kidney development, by causing changes to the renal interstitium that leads to fibrocystic disease pathologies. Yet, it remains unknown how mutations in centrosome genes impact kidney interstitial cells. Here, we examined the consequences of defective centrosome biogenesis on stromal progenitor cell growth, differentiation and fate. Conditional deletion of Cep120 , a ciliopathy gene essential for centrosome duplication, in the stromal mesenchyme resulted in reduced abundance of pericytes, interstitial fibroblasts and mesangial cells. This was due to delayed mitosis, increased apoptosis, and changes in Wnt and Hedgehog signaling essential for differentiation of stromal lineages. Cep120 ablation resulted in hypoplastic kidneys with medullary atrophy and delayed nephron maturation. Finally, centrosome loss in the interstitium sensitized kidneys of adult mice, causing rapid fibrosis via enhanced TGF-β/Smad3-Gli2 signaling after renal injury. Our study defines the cellular and developmental defects caused by centrosome dysfunction in embryonic kidney stroma. Highlights Defective centrosome biogenesis in kidney stroma causes:Reduced abundance of stromal progenitors, interstitial and mesangial cell populationsDefects in cell-autonomous and paracrine signalingAbnormal/delayed nephrogenesis and tubular dilationsAccelerates injury-induced fibrosis via defective TGF-β/Smad3-Gli2 signaling axis.
Collapse
|
|
9
|
Hannaford MR, Liu R, Billington N, Swider ZT, Galletta BJ, Fagerstrom CJ, Combs C, Sellers JR, Rusan NM. Pericentrin interacts with Kinesin-1 to drive centriole motility. J Cell Biol 2022; 221:e202112097. [PMID: 35929834 PMCID: PMC9361567 DOI: 10.1083/jcb.202112097] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2021] [Revised: 06/02/2022] [Accepted: 07/12/2022] [Indexed: 12/23/2022] Open
Abstract
Centrosome positioning is essential for their function. Typically, centrosomes are transported to various cellular locations through the interaction of centrosomal microtubules (MTs) with motor proteins anchored at the cortex or the nuclear surface. However, it remains unknown how centrioles migrate in cellular contexts in which they do not nucleate MTs. Here, we demonstrate that during interphase, inactive centrioles move directly along the interphase MT network as Kinesin-1 cargo. We identify Pericentrin-Like-Protein (PLP) as a novel Kinesin-1 interacting molecule essential for centriole motility. In vitro assays show that PLP directly interacts with the cargo binding domain of Kinesin-1, allowing PLP to migrate on MTs. Binding assays using purified proteins revealed that relief of Kinesin-1 autoinhibition is critical for its interaction with PLP. Finally, our studies of neural stem cell asymmetric divisions in the Drosophila brain show that the PLP-Kinesin-1 interaction is essential for the timely separation of centrioles, the asymmetry of centrosome activity, and the age-dependent centrosome inheritance.
Collapse
Affiliation(s)
- Matthew R. Hannaford
- Cell and Developmental Biology Center, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD
| | - Rong Liu
- Cell and Developmental Biology Center, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD
| | - Neil Billington
- Cell and Developmental Biology Center, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD
| | - Zachary T. Swider
- Cell and Developmental Biology Center, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD
| | - Brian J. Galletta
- Cell and Developmental Biology Center, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD
| | - Carey J. Fagerstrom
- Cell and Developmental Biology Center, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD
| | - Christian Combs
- Cell and Developmental Biology Center, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD
| | - James R. Sellers
- Cell and Developmental Biology Center, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD
| | - Nasser M. Rusan
- Cell and Developmental Biology Center, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD
| |
Collapse
|
|
10
|
A Nuclear Belt Fastens on Neural Cell Fate. Cells 2022; 11:cells11111761. [PMID: 35681456 PMCID: PMC9179901 DOI: 10.3390/cells11111761] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Revised: 05/20/2022] [Accepted: 05/21/2022] [Indexed: 12/22/2022] Open
Abstract
Successful embryonic and adult neurogenesis require proliferating neural stem and progenitor cells that are intrinsically and extrinsically guided into a neuronal fate. In turn, migration of new-born neurons underlies the complex cytoarchitecture of the brain. Proliferation and migration are therefore essential for brain development, homeostasis and function in adulthood. Among several tightly regulated processes involved in brain formation and function, recent evidence points to the nuclear envelope (NE) and NE-associated components as critical new contributors. Classically, the NE was thought to merely represent a barrier mediating selective exchange between the cytoplasm and nucleoplasm. However, research over the past two decades has highlighted more sophisticated and diverse roles for NE components in progenitor fate choice and migration of their progeny by tuning gene expression via interactions with chromatin, transcription factors and epigenetic factors. Defects in NE components lead to neurodevelopmental impairments, whereas age-related changes in NE components are proposed to influence neurodegenerative diseases. Thus, understanding the roles of NE components in brain development, maintenance and aging is likely to reveal new pathophysiological mechanisms for intervention. Here, we review recent findings for the previously underrepresented contribution of the NE in neuronal commitment and migration, and envision future avenues for investigation.
Collapse
|
|
11
|
Abstract
Ageing, death, and potential immortality lie at the heart of biology, but two seemingly incompatible paradigms coexist in different research communities and have done since the nineteenth century. The universal senescence paradigm sees senescence as inevitable in all cells. Damage accumulates. The potential immortality paradigm sees some cells as potentially immortal, especially unicellular organisms, germ cells and cancerous cells. Recent research with animal cells, yeasts and bacteria show that damaged cell constituents do in fact build up, but can be diluted by growth and cell division, especially by asymmetric cell division. By contrast, mammalian embryonic stem cells and many cancerous and 'immortalized' cell lines divide symmetrically, and yet replicate indefinitely. How do they acquire their potential immortality? I suggest they are rejuvenated by excreting damaged cell constituents in extracellular vesicles. If so, our understanding of cellular senescence, rejuvenation and potential immortality could be brought together in a new synthesis, which I call the cellular rejuvenation hypothesis: damaged cell constituents build up in all cells, but cells can be rejuvenated either by growth and cell division or, in 'immortal' cell lines, by excreting damaged cell constituents. In electronic supplementary material, appendix, I outline nine ways in which this hypothesis could be tested.
Collapse
|
|
12
|
Centrosomes and Centrosome Equivalents in Other Systems. THE CENTROSOME AND ITS FUNCTIONS AND DYSFUNCTIONS 2022; 235:85-104. [DOI: 10.1007/978-3-031-20848-5_9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
|
|
13
|
Schuster T, Geiger H. Septins in Stem Cells. Front Cell Dev Biol 2021; 9:801507. [PMID: 34957123 PMCID: PMC8695968 DOI: 10.3389/fcell.2021.801507] [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: 10/25/2021] [Accepted: 11/24/2021] [Indexed: 12/01/2022] Open
Abstract
Septins were first described in yeast. Due to extensive research in non-yeast cells, Septins are now recognized across all species as important players in the regulation of the cytoskeleton, in the establishment of polarity, for migration, vesicular trafficking and scaffolding. Stem cells are primarily quiescent cells, and this actively maintained quiescent state is critical for proper stem cell function. Equally important though, stem cells undergo symmetric or asymmetric division, which is likely linked to the level of symmetry found in the mother stem cell. Due to the ability to organize barriers and be able to break symmetry in cells, Septins are thought to have a significant impact on organizing quiescence as well as the mode (symmetric vs asymmetric) of stem cell division to affect self-renewal versus differentiation. Mechanisms of regulating mammalian quiescence and symmetry breaking by Septins are though still somewhat elusive. Within this overview article, we summarize current knowledge on the role of Septins in stem cells ranging from yeast to mice especially with respect to quiescence and asymmetric division, with a special focus on hematopoietic stem cells.
Collapse
Affiliation(s)
| | - Hartmut Geiger
- Institute of Molecular Medicine, Ulm University, Ulm, Germany
| |
Collapse
|
|
14
|
Goutas A, Trachana V. Stem cells' centrosomes: How can organelles identified 130 years ago contribute to the future of regenerative medicine? World J Stem Cells 2021; 13:1177-1196. [PMID: 34630857 PMCID: PMC8474719 DOI: 10.4252/wjsc.v13.i9.1177] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 05/03/2021] [Accepted: 08/09/2021] [Indexed: 02/06/2023] Open
Abstract
At the core of regenerative medicine lies the expectation of repair or replacement of damaged tissues or whole organs. Donor scarcity and transplant rejection are major obstacles, and exactly the obstacles that stem cell-based therapy promises to overcome. These therapies demand a comprehensive understanding of the asymmetric division of stem cells, i.e. their ability to produce cells with identical potency or differentiated cells. It is believed that with better understanding, researchers will be able to direct stem cell differentiation. Here, we describe extraordinary advances in manipulating stem cell fate that show that we need to focus on the centrosome and the centrosome-derived primary cilium. This belief comes from the fact that this organelle is the vehicle that coordinates the asymmetric division of stem cells. This is supported by studies that report the significant role of the centrosome/cilium in orchestrating signaling pathways that dictate stem cell fate. We anticipate that there is sufficient evidence to place this organelle at the center of efforts that will shape the future of regenerative medicine.
Collapse
Affiliation(s)
- Andreas Goutas
- Department of Biology, Faculty of Medicine, University of Thessaly, Larisa 41500, Biopolis, Greece
| | - Varvara Trachana
- Department of Biology, Faculty of Medicine, University of Thessaly, Larisa 41500, Biopolis, Greece.
| |
Collapse
|
|
15
|
Drosophila female germline stem cells undergo mitosis without nuclear breakdown. Curr Biol 2021; 31:1450-1462.e3. [PMID: 33548191 DOI: 10.1016/j.cub.2021.01.033] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Revised: 11/18/2020] [Accepted: 01/11/2021] [Indexed: 02/02/2023]
Abstract
Stem cell homeostasis requires nuclear lamina (NL) integrity. In Drosophila germ cells, compromised NL integrity activates the ataxia telangiectasia and Rad3-related (ATR) and checkpoint kinase 2 (Chk2) checkpoint kinases, blocking germ cell differentiation and causing germline stem cell (GSC) loss. Checkpoint activation occurs upon loss of either the NL protein emerin or its partner barrier-to-autointegration factor, two proteins required for nuclear reassembly at the end of mitosis. Here, we examined how mitosis contributes to NL structural defects linked to checkpoint activation. These analyses led to the unexpected discovery that wild-type female GSCs utilize a non-canonical mode of mitosis, one that retains a permeable but intact nuclear envelope and NL. We show that the interphase NL is remodeled during mitosis for insertion of centrosomes that nucleate the mitotic spindle within the confines of the nucleus. We show that depletion or loss of NL components causes mitotic defects, including compromised chromosome segregation associated with altered centrosome positioning and structure. Further, in emerin mutant GSCs, centrosomes remain embedded in the interphase NL. Notably, these embedded centrosomes carry large amounts of pericentriolar material and nucleate astral microtubules, revealing a role for emerin in the regulation of centrosome structure. Epistasis studies demonstrate that defects in centrosome structure are upstream of checkpoint activation, suggesting that these centrosome defects might trigger checkpoint activation and GSC loss. Connections between NL proteins and centrosome function have implications for mechanisms associated with NL dysfunction in other stem cell populations, including NL-associated diseases, such as laminopathies.
Collapse
|
|
16
|
Abstract
The centrosome is a unique organelle: the semi-conservative nature of its duplication generates an inherent asymmetry between ‘mother’ and ‘daughter’ centrosomes, which differ in their age. This asymmetry has captivated many cell biologists, but its meaning has remained enigmatic. In the last two decades, many stem cell types have been shown to display stereotypical inheritance of either the mother or daughter centrosome. These observations have led to speculation that the mother and daughter centrosomes bear distinct information, contributing to differential cell fates during asymmetric cell divisions. This review summarizes recent progress and discusses how centrosome asymmetry may promote asymmetric fates during stem cell divisions.
Collapse
Affiliation(s)
- Cuie Chen
- Life Sciences Institute, Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI, USA
| | - Yukiko M Yamashita
- Life Sciences Institute, Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI, USA.,Whitehead Institute for Biomedical Research, Department of Biology, Massachusetts Institute of Technology, Howard Hughes Medical Institute, Cambridge, MA, USA
| |
Collapse
|
|
17
|
Royall LN, Jessberger S. How stem cells remember their past. Curr Opin Cell Biol 2021; 69:17-22. [PMID: 33429112 DOI: 10.1016/j.ceb.2020.12.008] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2020] [Revised: 11/26/2020] [Accepted: 12/12/2020] [Indexed: 12/16/2022]
Abstract
Somatic stem cells are required for tissue development, homeostasis, and repair. Recent data suggested that previous biographical experiences of individual stem cells influence their behavior in the context of tissue formation and govern stem cell responses to external stimuli. Here we provide a concise review how a cell's biography, for example, previous rounds of cell divisions or the age-dependent accumulation of cellular damage, is remembered in stem cells and how previous experiences affect the segregation of cellular components, thus guiding cellular behavior in vertebrate stem cells. Further, we suggest future directions of research that may help to unravel the molecular underpinnings of how past experiences guide future cellular behavior.
Collapse
Affiliation(s)
- Lars N Royall
- Laboratory of Neural Plasticity, Faculties of Medicine and Science, Brain Research Institute, University of Zurich, 8057, Zurich, Switzerland
| | - Sebastian Jessberger
- Laboratory of Neural Plasticity, Faculties of Medicine and Science, Brain Research Institute, University of Zurich, 8057, Zurich, Switzerland.
| |
Collapse
|
|
18
|
Molzahn CM, Mayor T. Protein Aggregation Triggered by Rewired Protein Homeostasis during Neuronal Differentiation. Mol Cell 2020; 78:195-196. [PMID: 32302540 DOI: 10.1016/j.molcel.2020.03.028] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
In this issue of Molecular Cell, Vonk et al. (2020) and Thiruvalluvan et al. (2020) identify key chaperones that confer resistance to protein aggregation in neural stem cells and become reduced upon differentiation.
Collapse
Affiliation(s)
- Cristen M Molzahn
- Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada; Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada
| | - Thibault Mayor
- Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada; Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada.
| |
Collapse
|
|
19
|
Vora SM, Fassler JS, Phillips BT. Centrosomes are required for proper β-catenin processing and Wnt response. Mol Biol Cell 2020; 31:1951-1961. [PMID: 32583737 PMCID: PMC7525817 DOI: 10.1091/mbc.e20-02-0139] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
The Wnt/β-catenin signaling pathway is central to metazoan development and routinely dysregulated in cancer. Wnt/β-catenin signaling initiates transcriptional reprogramming upon stabilization of the transcription factor β-catenin, which is otherwise posttranslationally processed by a destruction complex and degraded by the proteasome. Since various Wnt signaling components are enriched at centrosomes, we examined the functional contribution of centrosomes to Wnt signaling, β-catenin regulation, and posttranslational modifications. In HEK293 cells depleted of centrosomes we find that β-catenin synthesis and degradation rates are unaffected but that the normal accumulation of β-catenin in response to Wnt signaling is attenuated. This is due to accumulation of a novel high-molecular-weight form of phosphorylated β-catenin that is constitutively degraded in the absence of Wnt. Wnt signaling operates by inhibiting the destruction complex and thereby reducing destruction complex–phosphorylated β-catenin, but high-molecular-weight β-catenin is unexpectedly increased by Wnt signaling. Therefore these studies have identified a pool of β-catenin effectively shielded from regulation by Wnt. We present a model whereby centrosomes prevent inappropriate β-catenin modifications that antagonize normal stabilization by Wnt signals.
Collapse
Affiliation(s)
- Setu M Vora
- Department of Biology, University of Iowa, Iowa City, IA 52242-1324
| | - Jan S Fassler
- Department of Biology, University of Iowa, Iowa City, IA 52242-1324
| | - Bryan T Phillips
- Department of Biology, University of Iowa, Iowa City, IA 52242-1324
| |
Collapse
|
|
20
|
von der Heyde EL, Hallmann A. Babo1, formerly Vop1 and Cop1/2, is no eyespot photoreceptor but a basal body protein illuminating cell division in Volvox carteri. THE PLANT JOURNAL : FOR CELL AND MOLECULAR BIOLOGY 2020; 102:276-298. [PMID: 31778231 DOI: 10.1111/tpj.14623] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Revised: 10/29/2019] [Accepted: 11/19/2019] [Indexed: 06/10/2023]
Abstract
In photosynthetic organisms many processes are light dependent and sensing of light requires light-sensitive proteins. The supposed eyespot photoreceptor protein Babo1 (formerly Vop1) has previously been classified as an opsin due to the capacity for binding retinal. Here, we analyze Babo1 and provide evidence that it is no opsin. Due to the localization at the basal bodies, the former Vop1 and Cop1/2 proteins were renamed V.c. Babo1 and C.r. Babo1. We reveal a large family of more than 60 Babo1-related proteins from a wide range of species. The detailed subcellular localization of fluorescence-tagged Babo1 shows that it accumulates at the basal apparatus. More precisely, it is located predominantly at the basal bodies and to a lesser extent at the four strands of rootlet microtubules. We trace Babo1 during basal body separation and cell division. Dynamic structural rearrangements of Babo1 particularly occur right before the first cell division. In four-celled embryos Babo1 was exclusively found at the oldest basal bodies of the embryo and on the corresponding d-roots. The unequal distribution of Babo1 in four-celled embryos could be an integral part of a geometrical system in early embryogenesis, which establishes the anterior-posterior polarity and influences the spatial arrangement of all embryonic structures and characteristics. Due to its retinal-binding capacity, Babo1 could also be responsible for the unequal distribution of retinoids, knowing that such concentration gradients of retinoids can be essential for the correct patterning during embryogenesis of more complex organisms. Thus, our findings push the Babo1 research in another direction.
Collapse
Affiliation(s)
- Eva L von der Heyde
- Department of Cellular and Developmental Biology of Plants, University of Bielefeld, Universitätsstr 25, 33615, Bielefeld, Germany
| | - Armin Hallmann
- Department of Cellular and Developmental Biology of Plants, University of Bielefeld, Universitätsstr 25, 33615, Bielefeld, Germany
| |
Collapse
|
|
21
|
Wang Y, Lo WC, Chou CS. Modelling stem cell ageing: a multi-compartment continuum approach. ROYAL SOCIETY OPEN SCIENCE 2020; 7:191848. [PMID: 32269805 PMCID: PMC7137970 DOI: 10.1098/rsos.191848] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Accepted: 02/10/2020] [Indexed: 06/11/2023]
Abstract
Stem cells are important to generate all specialized tissues at an early life stage, and in some systems, they also have repair functions to replenish the adult tissues. Repeated cell divisions lead to the accumulation of molecular damage in stem cells, which are commonly recognized as drivers of ageing. In this paper, a novel model is proposed to integrate stem cell proliferation and differentiation with damage accumulation in the stem cell ageing process. A system of two structured PDEs is used to model the population densities of stem cells (including all multiple progenitors) and terminally differentiated (TD) cells. In this system, cell cycle progression and damage accumulation are modelled by continuous dynamics, and damage segregation between daughter cells is considered at each division. Analysis and numerical simulations are conducted to study the steady-state populations and stem cell damage distributions under different damage segregation strategies. Our simulations suggest that equal distribution of the damaging substance between stem cells in a symmetric renewal and less damage retention in stem cells in the asymmetric division are favourable strategies, which reduce the death rate of the stem cells and increase the TD cell populations. Moreover, asymmetric damage segregation in stem cells leads to less concentrated damage distribution in the stem cell population, which may be more robust to the stochastic changes in the damage. The feedback regulation from stem cells can reduce oscillations and population overshoot in the process, and improve the fitness of stem cells by increasing the percentage of cells with less damage in the stem cell population.
Collapse
Affiliation(s)
- Yanli Wang
- Department of Mathematics, The Ohio State University, Columbus, OH, USA
| | - Wing-Cheong Lo
- Department of Mathematics, City University of Hong Kong, Hong Kong, People’s Republic of China
| | - Ching-Shin Chou
- Department of Mathematics, The Ohio State University, Columbus, OH, USA
| |
Collapse
|
|
22
|
Abstract
Asymmetric cell division (ACD) is a conserved strategy for achieving cell diversity. A cell can undergo an intrinsic ACD through asymmetric segregation of cell fate determinants or cellular organelles. Recently, a new biophysical concept known as biomolecular phase separation, through which proteins and/or RNAs autonomously form a highly concentrated non-membrane-enclosed compartment via multivalent interactions, has provided new insights into the assembly and regulation of many membrane-less or membrane-attached organelles. Intriguingly, biomolecular phase separation is suggested to drive asymmetric condensation of cell fate determinants during ACD as well as organization of cellular organelles involved in ACD. In this Perspective, I first summarize recent findings on the molecular basis governing intrinsic ACD. Then I will discuss how ACD might be regulated by formation of dense molecular assemblies via phase separation.
Collapse
Affiliation(s)
- Wenyu Wen
- Department of Neurosurgery, Huashan Hospital, Institutes of Biomedical Sciences, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, School of Basic Medical Sciences , Shanghai Medical College of Fudan University , Shanghai 200032 , China
| |
Collapse
|
|
23
|
Riparbelli MG, Persico V, Callaini G. A transient microtubule-based structure uncovers a new intrinsic asymmetry between the mother centrioles in the early Drosophila spermatocytes. Cytoskeleton (Hoboken) 2019; 75:472-480. [PMID: 30381895 DOI: 10.1002/cm.21503] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2018] [Revised: 09/27/2018] [Accepted: 10/25/2018] [Indexed: 12/23/2022]
Abstract
Parent centrioles are characterized in most organisms by individual morphological traits and have distinct asymmetries that provide different functional properties. By contrast, mother and daughter centrioles are morphologically undistinguishable during Drosophila male gametogenesis. Here we report the presence of previously unrecognized microtubule-based structures that extend into the peripheral cytoplasm of the Drosophila polar spermatocytes at the onset of the first meiosis and are positive for the typical centriolar protein Sas-4 and for the kinesin-like protein Klp10A. These structures have a short lifespan and are no longer found in early apolar spermatocytes. Remarkably, each polar spermatocyte holds only one microtubule-based structure that is associated with one of the sister centriole pairs and specifically with the mother centriole. These findings reveal an inherent asymmetry between the parent centrioles at the onset of male meiosis and also uncover unexpected functional properties between the mother centrioles of the same cells.
Collapse
|
|
24
|
Abstract
Longevity reflects the ability to maintain homeostatic conditions necessary for life as an organism ages. A long-lived organism must contend not only with environmental hazards but also with internal entropy and macromolecular damage that result in the loss of fitness during ageing, a phenomenon known as senescence. Although central to many of the core concepts in biology, ageing and longevity have primarily been investigated in sexually reproducing, multicellular organisms. However, growing evidence suggests that microorganisms undergo senescence, and can also exhibit extreme longevity. In this Review, we integrate theoretical and empirical insights to establish a unified perspective on senescence and longevity. We discuss the evolutionary origins, genetic mechanisms and functional consequences of microbial ageing. In addition to having biomedical implications, insights into microbial ageing shed light on the role of ageing in the origin of life and the upper limits to longevity.
Collapse
|
|
25
|
Oh D, Houston DW. RNA Localization in the Vertebrate Oocyte: Establishment of Oocyte Polarity and Localized mRNA Assemblages. Results Probl Cell Differ 2019; 63:189-208. [PMID: 28779319 PMCID: PMC6538070 DOI: 10.1007/978-3-319-60855-6_9] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
RNA localization is a fundamental mechanism for controlling cell structure and function. Early development in fish and amphibians requires the localization of specific mRNAs to establish the initial differences in cell fates prior to the onset of zygotic genome activation. RNA localization in these oocytes (e.g., Xenopus and zebrafish) requires that animal-vegetal polarity be established early in oogenesis, mediated by formation of the Balbiani body/mitochondrial cloud. This structure serves as a platform for assembly and transport of germline determinants to the future vegetal pole and also sets up the machinery for the localization of non-germline transcripts later in oogenesis. Understanding these polarization and localization mechanisms is critical for understanding the basis for early embryonic development in these organisms and also for understanding the role of RNA compartmentalization in animal gametogenesis. Here we outline recent advances in elucidating the molecular basis for the establishment of oocyte polarity at the level of Balbiani body assembly as well as the formation of RNP assemblies for early and late pathway mRNA localization in the oocyte.
Collapse
Affiliation(s)
- Denise Oh
- Department of Biology, The University of Iowa, 257 BB, Iowa City, IA, 52242, USA
| | - Douglas W Houston
- Department of Biology, The University of Iowa, 257 BB, Iowa City, IA, 52242, USA.
| |
Collapse
|
|
26
|
Proenca AM, Rang CU, Qiu A, Shi C, Chao L. Cell aging preserves cellular immortality in the presence of lethal levels of damage. PLoS Biol 2019; 17:e3000266. [PMID: 31120870 PMCID: PMC6532838 DOI: 10.1371/journal.pbio.3000266] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Accepted: 04/29/2019] [Indexed: 12/13/2022] Open
Abstract
Cellular aging, a progressive functional decline driven by damage accumulation, often culminates in the mortality of a cell lineage. Certain lineages, however, are able to sustain long-lasting immortality, as prominently exemplified by stem cells. Here, we show that Escherichia coli cell lineages exhibit comparable patterns of mortality and immortality. Through single-cell microscopy and microfluidic techniques, we find that these patterns are explained by the dynamics of damage accumulation and asymmetric partitioning between daughter cells. At low damage accumulation rates, both aging and rejuvenating lineages retain immortality by reaching their respective states of physiological equilibrium. We show that both asymmetry and equilibrium are present in repair mutants lacking certain repair chaperones, suggesting that intact repair capacity is not essential for immortal proliferation. We show that this growth equilibrium, however, is displaced by extrinsic damage in a dosage-dependent response. Moreover, we demonstrate that aging lineages become mortal when damage accumulation rates surpass a threshold, whereas rejuvenating lineages within the same population remain immortal. Thus, the processes of damage accumulation and partitioning through asymmetric cell division are essential in the determination of proliferative mortality and immortality in bacterial populations. This study provides further evidence for the characterization of cellular aging as a general process, affecting prokaryotes and eukaryotes alike and according to similar evolutionary constraints. A study of Escherichia coli shows that bacterial lineages maintain replicative immortality by reaching an equilibrium between aging and rejuvenation; when this equilibrium is disrupted, aging lineages cross their immortality threshold, becoming mortal, while rejuvenating lineages are favored by asymmetry and retain immortality within the same population.
Collapse
Affiliation(s)
- Audrey Menegaz Proenca
- Section of Ecology, Behavior and Evolution, Division of Biological Sciences, University of California, San Diego, La Jolla, California, United States of America
- CAPES Foundation, Ministry of Education of Brazil, Brasilia, Brazil
- * E-mail: (AMP); (LC)
| | - Camilla Ulla Rang
- Section of Ecology, Behavior and Evolution, Division of Biological Sciences, University of California, San Diego, La Jolla, California, United States of America
| | - Andrew Qiu
- Section of Ecology, Behavior and Evolution, Division of Biological Sciences, University of California, San Diego, La Jolla, California, United States of America
| | - Chao Shi
- Section of Ecology, Behavior and Evolution, Division of Biological Sciences, University of California, San Diego, La Jolla, California, United States of America
| | - Lin Chao
- Section of Ecology, Behavior and Evolution, Division of Biological Sciences, University of California, San Diego, La Jolla, California, United States of America
- * E-mail: (AMP); (LC)
| |
Collapse
|
|
27
|
Asymmetric Inheritance of Cell Fate Determinants: Focus on RNA. Noncoding RNA 2019; 5:ncrna5020038. [PMID: 31075989 PMCID: PMC6630313 DOI: 10.3390/ncrna5020038] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Revised: 04/30/2019] [Accepted: 05/06/2019] [Indexed: 12/20/2022] Open
Abstract
During the last decade, and mainly primed by major developments in high-throughput sequencing technologies, the catalogue of RNA molecules harbouring regulatory functions has increased at a steady pace. Current evidence indicates that hundreds of mammalian RNAs have regulatory roles at several levels, including transcription, translation/post-translation, chromatin structure, and nuclear architecture, thus suggesting that RNA molecules are indeed mighty controllers in the flow of biological information. Therefore, it is logical to suggest that there must exist a series of molecular systems that safeguard the faithful inheritance of RNA content throughout cell division and that those mechanisms must be tightly controlled to ensure the successful segregation of key molecules to the progeny. Interestingly, whilst a handful of integral components of mammalian cells seem to follow a general pattern of asymmetric inheritance throughout division, the fate of RNA molecules largely remains a mystery. Herein, we will discuss current concepts of asymmetric inheritance in a wide range of systems, including prions, proteins, and finally RNA molecules, to assess overall the biological impact of RNA inheritance in cellular plasticity and evolutionary fitness.
Collapse
|
|
28
|
Rodriguez-Fernandez IA, Qi Y, Jasper H. Loss of a proteostatic checkpoint in intestinal stem cells contributes to age-related epithelial dysfunction. Nat Commun 2019; 10:1050. [PMID: 30837466 PMCID: PMC6401111 DOI: 10.1038/s41467-019-08982-9] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2017] [Accepted: 02/09/2019] [Indexed: 01/08/2023] Open
Abstract
A decline in protein homeostasis (proteostasis) has been proposed as a hallmark of aging. Somatic stem cells (SCs) uniquely maintain their proteostatic capacity through mechanisms that remain incompletely understood. Here, we describe and characterize a ‘proteostatic checkpoint’ in Drosophila intestinal SCs (ISCs). Following a breakdown of proteostasis, ISCs coordinate cell cycle arrest with protein aggregate clearance by Atg8-mediated activation of the Nrf2-like transcription factor cap-n-collar C (CncC). CncC induces the cell cycle inhibitor Dacapo and proteolytic genes. The capacity to engage this checkpoint is lost in ISCs from aging flies, and we show that it can be restored by treating flies with an Nrf2 activator, or by over-expression of CncC or Atg8a. This limits age-related intestinal barrier dysfunction and can result in lifespan extension. Our findings identify a new mechanism by which somatic SCs preserve proteostasis, and highlight potential intervention strategies to maintain regenerative homeostasis. Protein homeostasis maintenance (proteostasis) is critical for cell function, but declines during aging. Here the authors detail a proteostatic checkpoint in Drosophila intestinal stem cells coordinating cell cycle arrest with protein aggregate clearance, along with its role in aging related intestinal dysfunction.
Collapse
Affiliation(s)
- Imilce A Rodriguez-Fernandez
- Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA, 94945-1400, USA.,Immunology Discovery, Genentech, Inc., 1 DNA Way, South San Francisco, California, 94080, USA
| | - Yanyan Qi
- Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA, 94945-1400, USA
| | - Heinrich Jasper
- Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA, 94945-1400, USA. .,Immunology Discovery, Genentech, Inc., 1 DNA Way, South San Francisco, California, 94080, USA. .,Leibniz Institute on Aging - Fritz Lipmann Institute, Jena, 07745, Germany.
| |
Collapse
|
|
29
|
|
|
30
|
Abstract
For over a century, the centrosome has been an organelle more easily tracked than understood, and the study of its peregrinations within the cell remains a chief underpinning of its functional investigation. Increasing attention and new approaches have been brought to bear on mechanisms that control centrosome localization in the context of cleavage plane determination, ciliogenesis, directional migration, and immunological synapse formation, among other cellular and developmental processes. The Golgi complex, often linked with the centrosome, presents a contrasting case of a pleiomorphic organelle for which functional studies advanced somewhat more rapidly than positional tracking. However, Golgi orientation and distribution has emerged as an area of considerable interest with respect to polarized cellular function. This chapter will review our current understanding of the mechanism and significance of the positioning of these organelles.
Collapse
|
|
31
|
Xue Y, Acar M. Mechanisms for the epigenetic inheritance of stress response in single cells. Curr Genet 2018; 64:1221-1228. [PMID: 29846762 PMCID: PMC6215725 DOI: 10.1007/s00294-018-0849-1] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2018] [Revised: 05/27/2018] [Accepted: 05/28/2018] [Indexed: 12/31/2022]
Abstract
Cells have evolved to dynamically respond to different types of environmental and physiological stress conditions. The information about a previous stress stimulus experience by a mother cell can be passed to its descendants, allowing them to better adapt to and survive in new environments. In recent years, live-cell imaging combined with cell-lineage tracking approaches has elucidated many important principles that guide stress inheritance at the single-cell and population level. In this review, we summarize different strategies that cells can employ to pass the 'memory' of previous stress responses to their descendants. Among these strategies, we focus on a recent discovery of how specific features of Msn2 nucleo-cytoplasmic shuttling dynamics could be inherited across cell lineages. We also discuss how stress response can be transmitted to progenies through changes in chromatin and through partitioning of anti-stress factors and/or damaged macromolecules between mother and daughter cells during cell division. Finally, we highlight how emergent technologies will help address open questions in the field.
Collapse
Affiliation(s)
- Yuan Xue
- Department of Molecular Cellular and Developmental Biology, Yale University, 219 Prospect Street, New Haven, CT, 06511, USA
- Systems Biology Institute, Yale University, 850 West Campus Drive, West Haven, CT, 06516, USA
| | - Murat Acar
- Department of Molecular Cellular and Developmental Biology, Yale University, 219 Prospect Street, New Haven, CT, 06511, USA.
- Systems Biology Institute, Yale University, 850 West Campus Drive, West Haven, CT, 06516, USA.
- Interdepartmental Program in Computational Biology and Bioinformatics, Yale University, 300 George Street, Suite 501, New Haven, CT, 06511, USA.
- Department of Physics, Yale University, Prospect Street, New Haven, CT, 06511, USA.
| |
Collapse
|
|
32
|
Saade M, Blanco-Ameijeiras J, Gonzalez-Gobartt E, Martí E. A centrosomal view of CNS growth. Development 2018; 145:145/21/dev170613. [DOI: 10.1242/dev.170613] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
ABSTRACT
Embryonic development of the central nervous system (CNS) requires the proliferation of neural progenitor cells to be tightly regulated, allowing the formation of an organ with the right size and shape. This includes regulation of both the spatial distribution of mitosis and the mode of cell division. The centrosome, which is the main microtubule-organizing centre of animal cells, contributes to both of these processes. Here, we discuss the impact that centrosome-mediated control of cell division has on the shape of the overall growing CNS. We also review the intrinsic properties of the centrosome, both in terms of its molecular composition and its signalling capabilities, and discuss the fascinating notion that intrinsic centrosomal asymmetries in dividing neural progenitor cells are instructive for neurogenesis. Finally, we discuss the genetic links between centrosome dysfunction during development and the aetiology of microcephaly.
Collapse
Affiliation(s)
- Murielle Saade
- Department of Developmental Biology, Instituto de Biología Molecular de Barcelona, Parc Científic de Barcelona, Baldiri i Reixac 20, Barcelona 08028, Spain
| | - Jose Blanco-Ameijeiras
- Department of Developmental Biology, Instituto de Biología Molecular de Barcelona, Parc Científic de Barcelona, Baldiri i Reixac 20, Barcelona 08028, Spain
| | - Elena Gonzalez-Gobartt
- Department of Developmental Biology, Instituto de Biología Molecular de Barcelona, Parc Científic de Barcelona, Baldiri i Reixac 20, Barcelona 08028, Spain
| | - Elisa Martí
- Department of Developmental Biology, Instituto de Biología Molecular de Barcelona, Parc Científic de Barcelona, Baldiri i Reixac 20, Barcelona 08028, Spain
| |
Collapse
|
|
33
|
Venkei ZG, Yamashita YM. Emerging mechanisms of asymmetric stem cell division. J Cell Biol 2018; 217:3785-3795. [PMID: 30232100 PMCID: PMC6219723 DOI: 10.1083/jcb.201807037] [Citation(s) in RCA: 124] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2018] [Revised: 09/06/2018] [Accepted: 09/13/2018] [Indexed: 01/10/2023] Open
Abstract
Venkei and Yamashita summarize recent advances in our understanding of asymmetric stem cell division in tissue homeostasis. The asymmetric cell division of stem cells, which produces one stem cell and one differentiating cell, has emerged as a mechanism to balance stem cell self-renewal and differentiation. Elaborate cellular mechanisms that orchestrate the processes required for asymmetric cell divisions are often shared between stem cells and other asymmetrically dividing cells. During asymmetric cell division, cells must establish asymmetry/polarity, which is guided by varying degrees of intrinsic versus extrinsic cues, and use intracellular machineries to divide in a desired orientation in the context of the asymmetry/polarity. Recent studies have expanded our knowledge on the mechanisms of asymmetric cell divisions, revealing the previously unappreciated complexity in setting up the cellular and/or environmental asymmetry, ensuring binary outcomes of the fate determination. In this review, we summarize recent progress in understanding the mechanisms and regulations of asymmetric stem cell division.
Collapse
Affiliation(s)
- Zsolt G Venkei
- Life Sciences Institute, University of Michigan, Ann Arbor, MI
| | - Yukiko M Yamashita
- Life Sciences Institute, University of Michigan, Ann Arbor, MI .,Department of Cell and Developmental Biology, Medical School, University of Michigan, Ann Arbor, MI.,Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI
| |
Collapse
|
|
34
|
Age structure landscapes emerge from the equilibrium between aging and rejuvenation in bacterial populations. Nat Commun 2018; 9:3722. [PMID: 30213942 PMCID: PMC6137065 DOI: 10.1038/s41467-018-06154-9] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Accepted: 08/16/2018] [Indexed: 12/22/2022] Open
Abstract
The physiological asymmetry between daughters of a mother bacterium is produced by the inheritance of either old poles, carrying non-genetic damage, or newly synthesized poles. However, as bacteria display long-term growth stability leading to physiological immortality, there is controversy on whether asymmetry corresponds to aging. Here we show that deterministic age structure landscapes emerge from physiologically immortal bacterial lineages. Through single-cell microscopy and microfluidic techniques, we demonstrate that aging and rejuvenating bacterial lineages reach two distinct states of growth equilibria. These equilibria display stabilizing properties, which we quantified according to the compensatory trajectories of continuous lineages throughout generations. Finally, we show that the physiological asymmetry between aging and rejuvenating lineages produces complex age structure landscapes, resulting in a deterministic phenotypic heterogeneity that is neither an artifact of starvation nor a product of extrinsic damage. These findings indicate that physiological immortality and cellular aging can both be manifested in single celled organisms. Some daughter cells inherit the maternal old pole during bacterial division, but does this correspond to aging? Here, Proenca et al. show that constant patterns of aging and rejuvenation connect distinct growth equilibria within bacterial clonal populations, providing evidence for deterministic age structures.
Collapse
|
|
35
|
Bornens M. Cell polarity: having and making sense of direction-on the evolutionary significance of the primary cilium/centrosome organ in Metazoa. Open Biol 2018; 8:180052. [PMID: 30068565 PMCID: PMC6119866 DOI: 10.1098/rsob.180052] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Accepted: 07/05/2018] [Indexed: 12/13/2022] Open
Abstract
Cell-autonomous polarity in Metazoans is evolutionarily conserved. I assume that permanent polarity in unicellular eukaryotes is required for cell motion and sensory reception, integration of these two activities being an evolutionarily constrained function. Metazoans are unique in making cohesive multicellular organisms through complete cell divisions. They evolved a primary cilium/centrosome (PC/C) organ, ensuring similar functions to the basal body/flagellum of unicellular eukaryotes, but in different cells, or in the same cell at different moments. The possibility that this innovation contributed to the evolution of individuality, in being instrumental in the early specification of the germ line during development, is further discussed. Then, using the example of highly regenerative organisms like planarians, which have lost PC/C organ in dividing cells, I discuss the possibility that part of the remodelling necessary to reach a new higher-level unit of selection in multi-cellular organisms has been triggered by conflicts among individual cell polarities to reach an organismic polarity. Finally, I briefly consider organisms with a sensorimotor organ like the brain that requires exceedingly elongated polarized cells for its activity. I conclude that beyond critical consequences for embryo development, the conservation of cell-autonomous polarity in Metazoans had far-reaching implications for the evolution of individuality.
Collapse
Affiliation(s)
- Michel Bornens
- Institut Curie, PSL Research University, CNRS - UMR 144, 75005 Paris, France
| |
Collapse
|
|
36
|
Schneider KL, Nyström T, Widlund PO. Studying Spatial Protein Quality Control, Proteopathies, and Aging Using Different Model Misfolding Proteins in S. cerevisiae. Front Mol Neurosci 2018; 11:249. [PMID: 30083092 PMCID: PMC6064742 DOI: 10.3389/fnmol.2018.00249] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2018] [Accepted: 07/02/2018] [Indexed: 12/14/2022] Open
Abstract
Protein quality control (PQC) is critical to maintain a functioning proteome. Misfolded or toxic proteins are either refolded or degraded by a system of temporal quality control and can also be sequestered into aggregates or inclusions by a system of spatial quality control. Breakdown of this concerted PQC network with age leads to an increased risk for the onset of disease, particularly neurological disease. Saccharomyces cerevisiae has been used extensively to elucidate PQC pathways and general evolutionary conservation of the PQC machinery has led to the development of several useful S. cerevisiae models of human neurological diseases. Key to both of these types of studies has been the development of several different model misfolding proteins, which are used to challenge and monitor the PQC machinery. In this review, we summarize and compare the model misfolding proteins that have been used to specifically study spatial PQC in S. cerevisiae, as well as the misfolding proteins that have been shown to be subject to spatial quality control in S. cerevisiae models of human neurological diseases.
Collapse
Affiliation(s)
- Kara L Schneider
- Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Thomas Nyström
- Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Per O Widlund
- Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| |
Collapse
|
|
37
|
Abstract
β-Catenin is essential for embryonic development and required for cell renewal/regeneration in adult life. Cellular β-catenin exists in three different pools: membranous, cytoplasmic and nuclear. In this review, we focus on functions of the nuclear pool in relation to tumorigenesis. In the nucleus, beta-catenin functions as both activator and repressor of transcription in a context-dependent manner. It promotes cell proliferation and supports tumour growth by enhancing angiogenesis. β-Catenin-mediated signalling regulates cancer cell metabolism and is associated with tumour-initiating cells in multiple malignancies. In addition, it functions as both pro- and anti-apoptotic factor besides acting to inhibit recruitment of inflammatory anti-tumour T-cells. Thus, β-catenin appears to possess a multifaceted nuclear function that may significantly impact tumour initiation and progression.
Collapse
Affiliation(s)
- Raju Kumar
- Laboratory of Molecular Oncology, Centre for DNA Fingerprinting and Diagnostics, Hyderabad, India
| | | |
Collapse
|
|
38
|
Lengefeld J, Barral Y. Asymmetric Segregation of Aged Spindle Pole Bodies During Cell Division: Mechanisms and Relevance Beyond Budding Yeast? Bioessays 2018; 40:e1800038. [DOI: 10.1002/bies.201800038] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2018] [Revised: 05/21/2018] [Indexed: 01/21/2023]
Affiliation(s)
- Jette Lengefeld
- Institute of Biochemistry; ETH Zurich; Otto-Stern-Weg 3 8093 Zurich Switzerland
- David H. Koch Institute for Integrative Cancer Research; Massachusetts Institute of Technology; Cambridge, Massachusetts 02139 USA
| | - Yves Barral
- Institute of Biochemistry; ETH Zurich; Otto-Stern-Weg 3 8093 Zurich Switzerland
| |
Collapse
|
|
39
|
Centrosome Inheritance Does Not Regulate Cell Fate in Granule Neuron Progenitors of the Developing Cerebellum. THE CEREBELLUM 2018; 17:685-691. [DOI: 10.1007/s12311-018-0935-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
|
|
40
|
Kwon M, Kim JH, Rybak Y, Luna A, Choi CH, Chung JY, Hewitt SM, Adem A, Tubridy E, Lin J, Libutti SK. Reduced expression of FILIP1L, a novel WNT pathway inhibitor, is associated with poor survival, progression and chemoresistance in ovarian cancer. Oncotarget 2018; 7:77052-77070. [PMID: 27776341 PMCID: PMC5340232 DOI: 10.18632/oncotarget.12784] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2016] [Accepted: 10/17/2016] [Indexed: 12/15/2022] Open
Abstract
Filamin A interacting protein 1-like (FILIP1L) is an inhibitor of the canonical WNT pathway. WNT/β-catenin signaling and its downstream pathway, epithelial-to-mesenchymal transition (EMT), play a key role in ovarian cancer metastasis and chemoresistance. To study the clinical implications of FILIP1L in regulating the WNT/β-catenin pathway, the expression of FILIP1L, β-catenin, SNAIL and SLUG was analyzed by immunohistochemistry on tissue microarrays of 369 ovarian samples ranging from normal to metastatic. In addition, the results were validated in mouse model and in vitro cell culture. In the present study, we demonstrated that FILIP1L expression was inversely correlated with poor prognosis, stage and chemoresistance in ovarian cancer. Notably, low FILIP1L expression was independent negative prognostic factor with respect to overall and disease-free survival. FILIP1L inhibited peritoneal metastases in orthotopic mouse model. FILIP1L knockdown induced chemoresistance in ovarian cancer cells and this phenotype was rescued by simultaneous knockdown of FILIP1L and SLUG, an EMT activator. We also demonstrated that FILIP1L regulates β-catenin degradation. FILIP1L co-localizes with phospho-β-catenin and increases phospho-β-catenin at the centrosomes, destined for proteosomal degradation. Finally, we showed that FILIP1L regulates EMT. Overall, these findings suggest that FILIP1L promotes β-catenin degradation and suppresses EMT, thereby inhibiting metastases and chemoresistance. Our study provides the first clinical relevance of FILIP1L in human cancer, and suggests that FILIP1L may be a novel prognostic marker for chemotherapy in ovarian cancer patients. Further, the modulation of FILIP1L expression may have the potential to be a target for cancer therapy.
Collapse
Affiliation(s)
- Mijung Kwon
- Department of Surgery, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Jae-Hoon Kim
- Department of Obstetrics and Gynecology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 135-720, Korea.,Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul 135-720, Korea
| | - Yevangelina Rybak
- Department of Surgery, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Alex Luna
- Department of Surgery, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Chel Hun Choi
- Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea.,Experimental Pathology Laboratory, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Joon-Yong Chung
- Experimental Pathology Laboratory, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Stephen M Hewitt
- Experimental Pathology Laboratory, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Asha Adem
- Department of Surgery, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Elizabeth Tubridy
- Department of Surgery, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Juan Lin
- Division of Biostatistics, Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Steven K Libutti
- Department of Surgery, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| |
Collapse
|
|
41
|
Overexpressed ACBD3 has prognostic value in human breast cancer and promotes the self-renewal potential of breast cancer cells by activating the Wnt/beta-catenin signaling pathway. Exp Cell Res 2018; 363:39-47. [PMID: 29307786 DOI: 10.1016/j.yexcr.2018.01.003] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2017] [Revised: 12/25/2017] [Accepted: 01/02/2018] [Indexed: 01/30/2023]
Abstract
Acyl-CoA binding domain containing 3 (ACBD3) is involved in the maintenance of Golgi structure and function through its interaction with the integral membrane protein. However, the clinical significance and biological role of ACBD3 in breast cancer remain unclear. Herein, we found that the mRNA and protein levels of ACBD3 were markedly up-regulated in breast cancer cells and tissues. Immunohistochemical analysis of breast cancer tissues demonstrated that ACBD3 overexpression was significantly associated with advanced clinicopathological features. Univariate and multivariate analysis indicated that ACBD3 overexpression correlates with poor prognosis in breast cancer. Furthermore, overexpressing ACBD3 promoted, while silencing ACBD3 inhibited, self-renewal and tumorigenesis in breast cancer cells in vitro and in vivo respectively. Importantly, upregulating ACBD3 promoted the self-renewal and tumorigenesis of breast cancer cells via activating the Wnt/beta-catenin signaling, and the pro-self-renewal effect of ACBD3 in breast cancer was antagonized by the Wnt signaling inhibitor TCF4-siRNA and Lef1-siRNA.These findings indicate that ACBD3 may represent candidate therapeutic targets to enable the elimination of breast cancer stem cells, providing the preclinical proof-of-concept for the prevention and treatment of breast cancer.
Collapse
|
|
42
|
Stypulkowski E, Asangani IA, Witze ES. The depalmitoylase APT1 directs the asymmetric partitioning of Notch and Wnt signaling during cell division. Sci Signal 2018; 11:eaam8705. [PMID: 29295957 PMCID: PMC5914505 DOI: 10.1126/scisignal.aam8705] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Asymmetric cell division results in two distinctly fated daughter cells. A molecular hallmark of asymmetric division is the unequal partitioning of cell fate determinants. We have previously established that growth factor signaling promotes protein depalmitoylation to foster polarized protein localization, which, in turn, drives migration and metastasis. We report protein palmitoylation as a key mechanism for the asymmetric partitioning of the cell fate determinants Numb and β-catenin through the activity of the depalmitoylating enzyme APT1. Using point mutations, we showed that specific palmitoylated residues on Numb were required for its asymmetric localization. By live-cell imaging, we showed that reciprocal interactions between APT1 and the Rho family GTPase CDC42 promoted the asymmetric localization of Numb and β-catenin to the plasma membrane. This, in turn, restricted Notch- or Wnt-responsive transcriptional activity to one daughter cell. Moreover, we showed that altering APT1 abundance changed the transcriptional signatures of MDA-MB-231 triple receptor-negative breast cancer cells, similar to changes in Notch and β-catenin-mediated Wnt signaling. We also showed that loss of APT1 depleted a specific subpopulation of tumorigenic cells in colony formation assays. Together, our findings suggest that APT1-mediated depalmitoylation is a major mechanism of asymmetric cell division that maintains Notch- and Wnt-associated protein dynamics, gene expression, and cellular functions.
Collapse
Affiliation(s)
- Ewa Stypulkowski
- Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA 19104, USA
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Irfan A Asangani
- Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA 19104, USA
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Eric S Witze
- Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA
| |
Collapse
|
|
43
|
Florea M. Aging and immortality in unicellular species. Mech Ageing Dev 2017; 167:5-15. [PMID: 28844968 DOI: 10.1016/j.mad.2017.08.006] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2017] [Revised: 07/21/2017] [Accepted: 08/13/2017] [Indexed: 12/22/2022]
Abstract
It has been historically thought that in conditions that permit growth, most unicellular species do not to age. This was particularly thought to be the case for symmetrically dividing species, as such species lack a clear distinction between the soma and the germline. Despite this, studies of the symmetrically dividing species Escherichia coli and Schizosaccharomyces pombe have recently started to challenge this notion. They indicate that E. coli and S. pombe do age, but only when subjected to environmental stress. If true, this suggests that aging may be widespread among microbial species in general, and that studying aging in microbes may inform other long-standing questions in aging. This review examines the recent evidence for and against replicative aging in symmetrically dividing unicellular organisms, the mechanisms that underlie aging, why aging evolved in these species, and how microbial aging fits into the context of other questions in aging.
Collapse
Affiliation(s)
- Michael Florea
- Graduate School of Arts and Sciences, Harvard Medical School, 25 Shattuck St, Boston, MA 02115, USA.
| |
Collapse
|
|
44
|
Scerbo P, Marchal L, Kodjabachian L. Lineage commitment of embryonic cells involves MEK1-dependent clearance of pluripotency regulator Ventx2. eLife 2017; 6. [PMID: 28654420 PMCID: PMC5487210 DOI: 10.7554/elife.21526] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2016] [Accepted: 06/07/2017] [Indexed: 12/21/2022] Open
Abstract
During early embryogenesis, cells must exit pluripotency and commit to multiple lineages in all germ-layers. How this transition is operated in vivo is poorly understood. Here, we report that MEK1 and the Nanog-related transcription factor Ventx2 coordinate this transition. MEK1 was required to make Xenopus pluripotent cells competent to respond to all cell fate inducers tested. Importantly, MEK1 activity was necessary to clear the pluripotency protein Ventx2 at the onset of gastrulation. Thus, concomitant MEK1 and Ventx2 knockdown restored the competence of embryonic cells to differentiate. Strikingly, MEK1 appeared to control the asymmetric inheritance of Ventx2 protein following cell division. Consistently, when Ventx2 lacked a functional PEST-destruction motif, it was stabilized, displayed symmetric distribution during cell division and could efficiently maintain pluripotency gene expression over time. We suggest that asymmetric clearance of pluripotency regulators may represent an important mechanism to ensure the progressive assembly of primitive embryonic tissues. DOI:http://dx.doi.org/10.7554/eLife.21526.001
Collapse
Affiliation(s)
- Pierluigi Scerbo
- Institut de Biologie du Développement de Marseille, Aix Marseille Univ, CNRS, Marseille, France
| | - Leslie Marchal
- Institut de Biologie du Développement de Marseille, Aix Marseille Univ, CNRS, Marseille, France
| | - Laurent Kodjabachian
- Institut de Biologie du Développement de Marseille, Aix Marseille Univ, CNRS, Marseille, France
| |
Collapse
|
|
45
|
Hill SM, Hanzén S, Nyström T. Restricted access: spatial sequestration of damaged proteins during stress and aging. EMBO Rep 2017; 18:377-391. [PMID: 28193623 PMCID: PMC5331209 DOI: 10.15252/embr.201643458] [Citation(s) in RCA: 84] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Revised: 12/19/2016] [Accepted: 01/24/2017] [Indexed: 01/08/2023] Open
Abstract
The accumulation of damaged and aggregated proteins is a hallmark of aging and increased proteotoxic stress. To limit the toxicity of damaged and aggregated proteins and to ensure that the damage is not inherited by succeeding cell generations, a system of spatial quality control operates to sequester damaged/aggregated proteins into inclusions at specific protective sites. Such spatial sequestration and asymmetric segregation of damaged proteins have emerged as key processes required for cellular rejuvenation. In this review, we summarize findings on the nature of the different quality control sites identified in yeast, on genetic determinants required for spatial quality control, and on how aggregates are recognized depending on the stress generating them. We also briefly compare the yeast system to spatial quality control in other organisms. The data accumulated demonstrate that spatial quality control involves factors beyond the canonical quality control factors, such as chaperones and proteases, and opens up new venues in approaching how proteotoxicity might be mitigated, or delayed, upon aging.
Collapse
Affiliation(s)
- Sandra Malmgren Hill
- Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden
| | - Sarah Hanzén
- Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden
| | - Thomas Nyström
- Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden
| |
Collapse
|
|
46
|
Chen C, Inaba M, Venkei ZG, Yamashita YM. Klp10A, a stem cell centrosome-enriched kinesin, balances asymmetries in Drosophila male germline stem cell division. eLife 2016; 5:20977. [PMID: 27885983 PMCID: PMC5235350 DOI: 10.7554/elife.20977] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2016] [Accepted: 11/24/2016] [Indexed: 12/15/2022] Open
Abstract
Asymmetric stem cell division is often accompanied by stereotypical inheritance of the mother and daughter centrosomes. However, it remains unknown whether and how stem cell centrosomes are uniquely regulated and how this regulation may contribute to stem cell fate. Here we identify Klp10A, a microtubule-depolymerizing kinesin of the kinesin-13 family, as the first protein enriched in the stem cell centrosome in Drosophila male germline stem cells (GSCs). Depletion of klp10A results in abnormal elongation of the mother centrosomes in GSCs, suggesting the existence of a stem cell-specific centrosome regulation program. Concomitant with mother centrosome elongation, GSCs form asymmetric spindle, wherein the elongated mother centrosome organizes considerably larger half spindle than the other. This leads to asymmetric cell size, yielding a smaller differentiating daughter cell. We propose that klp10A functions to counteract undesirable asymmetries that may result as a by-product of achieving asymmetries essential for successful stem cell divisions. DOI:http://dx.doi.org/10.7554/eLife.20977.001
Collapse
Affiliation(s)
- Cuie Chen
- Department of Cell and Developmental Biology, Life Sciences Institute, Howard Hughes Medical Institute, University of Michigan, Ann Arbor, United States
| | - Mayu Inaba
- Department of Cell and Developmental Biology, Life Sciences Institute, Howard Hughes Medical Institute, University of Michigan, Ann Arbor, United States
| | - Zsolt G Venkei
- Department of Cell and Developmental Biology, Life Sciences Institute, Howard Hughes Medical Institute, University of Michigan, Ann Arbor, United States
| | - Yukiko M Yamashita
- Department of Cell and Developmental Biology, Life Sciences Institute, Howard Hughes Medical Institute, University of Michigan, Ann Arbor, United States
| |
Collapse
|
|
47
|
Moore DL, Jessberger S. Creating Age Asymmetry: Consequences of Inheriting Damaged Goods in Mammalian Cells. Trends Cell Biol 2016; 27:82-92. [PMID: 27717533 DOI: 10.1016/j.tcb.2016.09.007] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2016] [Revised: 09/10/2016] [Accepted: 09/13/2016] [Indexed: 12/15/2022]
Abstract
Accumulating evidence suggests that mammalian cells asymmetrically segregate cellular components ranging from genomic DNA to organelles and damaged proteins during cell division. Asymmetric inheritance upon mammalian cell division may be specifically important to ensure cellular fitness and propagate cellular potency to individual progeny, for example in the context of somatic stem cell division. We review here recent advances in the field and discuss potential effects and underlying mechanisms that mediate asymmetric segregation of cellular components during mammalian cell division.
Collapse
Affiliation(s)
- Darcie L Moore
- Department of Neuroscience, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705, USA.
| | - Sebastian Jessberger
- Brain Research Institute, Faculty of Medicine and Science, University of Zurich, 8057 Zurich, Switzerland.
| |
Collapse
|
|
48
|
Dpp/BMP2-4 Mediates Signaling from the D-Quadrant Organizer in a Spiralian Embryo. Curr Biol 2016; 26:2003-2010. [DOI: 10.1016/j.cub.2016.05.059] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2016] [Revised: 04/05/2016] [Accepted: 05/24/2016] [Indexed: 11/20/2022]
|
|
49
|
Vedel S, Nunns H, Košmrlj A, Semsey S, Trusina A. Asymmetric Damage Segregation Constitutes an Emergent Population-Level Stress Response. Cell Syst 2016; 3:187-198. [PMID: 27426983 DOI: 10.1016/j.cels.2016.06.008] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2015] [Revised: 04/05/2016] [Accepted: 06/16/2016] [Indexed: 01/15/2023]
Abstract
Asymmetric damage segregation (ADS) is a mechanism for increasing population fitness through non-random, asymmetric partitioning of damaged macromolecules at cell division. ADS has been reported across multiple organisms, though the measured effects on fitness of individuals are often small. Here, we introduce a cell-lineage-based framework that quantifies the population-wide effects of ADS and then verify our results experimentally in E. coli under heat and antibiotic stress. Using an experimentally validated mathematical model, we find that the beneficial effect of ADS increases with stress. In effect, low-damage subpopulations divide faster and amplify within the population acting like a positive feedback loop whose strength scales with stress. Analysis of protein aggregates shows that the degree of asymmetric inheritance is damage dependent in single cells. Together our results indicate that, despite small effects in single cell, ADS exerts a strong beneficial effect on the population level and arises from the redistribution of damage within a population, through both single-cell and population-level feedback.
Collapse
Affiliation(s)
- Søren Vedel
- Center for Models of Life, Niels Bohr Institute, University of Copenhagen, Blegdamsvej 17, 2100 Copenhagen, Denmark; Niels Bohr International Academy, Niels Bohr Institute, University of Copenhagen, Blegdamsvej 17, 2100 Copenhagen, Denmark.
| | - Harry Nunns
- Center for Models of Life, Niels Bohr Institute, University of Copenhagen, Blegdamsvej 17, 2100 Copenhagen, Denmark; Division of Biology and Biological Engineering, California Institute of Technology, 1200 E. California Boulevard, Pasadena, CA 91125, USA
| | - Andrej Košmrlj
- Department of Mechanical and Aerospace Engineering, Princeton University, Princeton, NJ 08544, USA
| | - Szabolcs Semsey
- Center for Models of Life, Niels Bohr Institute, University of Copenhagen, Blegdamsvej 17, 2100 Copenhagen, Denmark
| | - Ala Trusina
- Center for Models of Life, Niels Bohr Institute, University of Copenhagen, Blegdamsvej 17, 2100 Copenhagen, Denmark.
| |
Collapse
|
|
50
|
Vora SM, Phillips BT. The benefits of local depletion: The centrosome as a scaffold for ubiquitin-proteasome-mediated degradation. Cell Cycle 2016; 15:2124-2134. [PMID: 27294844 DOI: 10.1080/15384101.2016.1196306] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022] Open
Abstract
The centrosome is the major microtubule-organizing center in animal cells but is dispensable for proper microtubule spindle formation in many biological contexts and is thus thought to fulfill additional functions. Recent observations suggest that the centrosome acts as a scaffold for proteasomal degradation in the cell to regulate a variety of biological processes including cell fate acquisition, cell cycle control, stress response, and cell morphogenesis. Here, we review the body of studies indicating a role for the centrosome in promoting proteasomal degradation of ubiquitin-proteasome substrates and explore the functional relevance of this system in different biological contexts. We discuss a potential role for the centrosome in coordinating local degradation of proteasomal substrates, allowing cells to achieve stringent spatiotemporal control over various signaling processes.
Collapse
Affiliation(s)
- Setu M Vora
- a Department of Biological Sciences, University of Iowa , Iowa City , IA , USA
| | - Bryan T Phillips
- a Department of Biological Sciences, University of Iowa , Iowa City , IA , USA
| |
Collapse
|