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Lan YZ, Wu Z, Chen WJ, Yu XN, Wu HT, Liu J. Sine oculis homeobox homolog family function in gastrointestinal cancer: Progression and comprehensive analysis. World J Clin Oncol 2025; 16:97163. [PMID: 39867730 PMCID: PMC11528897 DOI: 10.5306/wjco.v16.i1.97163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2024] [Revised: 09/20/2024] [Accepted: 10/20/2024] [Indexed: 10/30/2024] Open
Abstract
The sine oculis homeobox homolog (SIX) family, a group of transcription factors characterized by a conserved DNA-binding homology domain, plays a critical role in orchestrating embryonic development and organogenesis across various organisms, including humans. Comprising six distinct members, from SIX1 to SIX6, each member contributes uniquely to the development and differentiation of diverse tissues and organs, underscoring the versatility of the SIX family. Dysregulation or mutations in SIX genes have been implicated in a spectrum of developmental disorders, as well as in tumor initiation and progression, highlighting their pivotal role in maintaining normal developmental trajectories and cellular functions. Efforts to target the transcriptional complex of the SIX gene family have emerged as a promising strategy to inhibit tumor development. While the development of inhibitors targeting this gene family is still in its early stages, the significant potential of such interventions holds promise for future therapeutic advances. Therefore, this review aimed to comprehensively explore the advancements in understanding the SIX family within gastrointestinal cancers, focusing on its critical role in normal organ development and its implications in gastrointestinal cancers, including gastric, pancreatic, colorectal cancer, and hepatocellular carcinomas. In conclusion, this review deepened the understanding of the functional roles of the SIX family and explored the potential of utilizing this gene family for the diagnosis, prognosis, and treatment of gastrointestinal cancers.
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Affiliation(s)
- Yang-Zheng Lan
- Department of The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Zheng Wu
- Department of The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Wen-Jia Chen
- Department of The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Xin-Ning Yu
- Department of General Surgery, First Affiliated Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Hua-Tao Wu
- Department of General Surgery, First Affiliated Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Jing Liu
- Department of The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
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2
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Lin Z, Cai W, Sun Y, Han B, Hu Y, Huang S, Li J, Chen X. Implications of ITCH-mediated ubiquitination of SIX1 on CDC27-cyclinB1 signaling in nasopharyngeal carcinoma. Sci Rep 2024; 14:24140. [PMID: 39406717 PMCID: PMC11480102 DOI: 10.1038/s41598-024-73239-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Accepted: 09/16/2024] [Indexed: 10/19/2024] Open
Abstract
Nasopharyngeal carcinoma (NPC) presents a significant medical challenge due to its high incidence rate and poor prognosis, which are attributed primarily to tumor metastasis and drug resistance. Sine oculis homeobox homolog 1 (SIX1) has been identified as a crucial target for cancer treatment. However, its role in NPC remains incompletely understood. This study investigated the mechanisms by which the degradation of the SIX1 protein, which is mediated by ubiquitin, affects the malignant characteristics of NPC throughout the cell cycle. Our findings reveal that reduced expression of the itchy E3 ubiquitin ligase E3 (ITCH) in NPC impedes the degradation of the SIX1 protein, leading to enhance oncogenic properties. Knockdown experiments which SIX1 was inhibited demonstrated a decrease in the proliferation, migration, and invasion of NPC cell lines, whereas overexpression of SIX1 yielded the opposite effects. Further experimental validation revealed that SIX1 promotes NPC progression via the cell division cycle 27 (CDC27)/cyclin B1 axis. These findings provide valuable insights into potential therapeutic targets and prognostic indicators for NPC treatment, emphasizing the ITCH/SIX1/CDC27/cyclin B1 axis as a promising target for novel therapies.
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Affiliation(s)
- Zehua Lin
- Department of Otolaryngology, Head and Neck Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, China
| | - Weisong Cai
- Department of Otolaryngology, Head and Neck Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, China
| | - Yuechen Sun
- Department of Otolaryngology, Head and Neck Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, China
| | - Baoai Han
- Department of Otolaryngology, Head and Neck Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, China
| | - Yifan Hu
- Department of Otolaryngology, Head and Neck Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, China
| | - Shuo Huang
- Department of Otolaryngology, Head and Neck Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, China
| | - Jun Li
- Department of Otolaryngology, Head and Neck Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, China.
| | - Xiong Chen
- Department of Otolaryngology, Head and Neck Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, China.
- Sleep Medicine Centre, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, China.
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3
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Bian Z, Benjamin MM, Bialousow L, Tian Y, Hobbs GA, Karan D, Choo YM, Hamann MT, Wang X. Targeting sine oculis homeoprotein 1 (SIX1): A review of oncogenic roles and potential natural product therapeutics. Heliyon 2024; 10:e33204. [PMID: 39022099 PMCID: PMC11252760 DOI: 10.1016/j.heliyon.2024.e33204] [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: 12/19/2023] [Revised: 06/16/2024] [Accepted: 06/17/2024] [Indexed: 07/20/2024] Open
Abstract
Sine oculis homeoprotein 1 (SIX1), a prominent representative of the homeodomain transcription factors within the SIX family, has attracted significant interest owing to its role in tumorigenesis, cancer progression, and prognostic assessments. Initially recognized for its pivotal role in embryonic development, SIX1 has emerged as a resurgent factor across a diverse set of mammalian cancers. Over the past two decades, numerous investigations have emphasized SIX1's dual significance as a developmental regulator and central player in oncogenic processes. A mounting body of evidence links SIX1 to the initiation of diverse cancers, encompassing enhanced cellular metabolism and advancement. This review provides an overview of the multifaceted roles of SIX1 in both normal development and oncogenic processes, emphasizing its importance as a possible therapeutic target and prognostic marker. Additionally, this review discusses the natural product agents that inhibit various pro-oncogenic mechanisms associated with SIX1.
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Affiliation(s)
- Zhiwei Bian
- School of Pharmacy, Lanzhou University, Lanzhou, 730000, Gansu, China
| | - Menny M. Benjamin
- Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, SC, USA
| | - Lucas Bialousow
- Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, SC, USA
| | - Yintai Tian
- School of Pharmacy, Lanzhou University, Lanzhou, 730000, Gansu, China
| | - G. Aaron Hobbs
- Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA
- Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, SC, USA
| | - Dev Karan
- Department of Pathology, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Yeun-Mun Choo
- Chemistry Department, Faculty of Science, University of Malaya, 50603, Kuala Lumpur, Malaysia
| | - Mark T. Hamann
- Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, SC, USA
| | - Xiaojuan Wang
- School of Pharmacy, Lanzhou University, Lanzhou, 730000, Gansu, China
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Zhang P, Zhang W, Wang X, Li L, Lin Y, Wu N, Mao R, Lin J, Kang M, Ding C. BCLAF1 drives esophageal squamous cell carcinoma progression through regulation of YTHDF2-dependent SIX1 mRNA degradation. Cancer Lett 2024; 591:216874. [PMID: 38636894 DOI: 10.1016/j.canlet.2024.216874] [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: 01/12/2024] [Revised: 04/01/2024] [Accepted: 04/07/2024] [Indexed: 04/20/2024]
Abstract
Esophageal cancer ranks among the most prevalent malignant tumors, and esophageal squamous cell carcinoma (ESCC) constitutes its predominant histological form. Despite its impact, a thorough insight into the molecular intricacies of ESCC's development is still incomplete, which hampers the advancement of targeted molecular diagnostics and treatments. Recently, B-cell lymphoma-2-associated transcription factor 1 (BCLAF1) has come under investigation for its potential involvement in tumor biology, yet its specific role and mechanism in ESCC remain unclear. In this study, we observed a marked increase in BCLAF1 expression in ESCC tissues, correlating with advanced tumor stages and inferior patient outcomes. Our comprehensive in vitro and in vivo studies show that BCLAF1 augments glycolytic activity and the proliferation, invasion, and spread of ESCC cells. By employing mass spectrometry, we identified YTHDF2 as a key protein interacting with BCLAF1 in ESCC, with further validation provided by colocalization, co-immunoprecipitation, and GST pull-down assay. Further investigations involving MeRIP-seq and RIP-seq, alongside transcriptomic analysis, highlighted SIX1 mRNA as a molecule significantly upregulated and modified by N6-methyladenosine (m6A) in BCLAF1 overexpressing cells. BCLAF1 was found to reduce the tumor-suppressive activities of YTHDF2, and its effects on promoting glycolysis and cancer progression were shown to hinge on SIX1 expression. This research establishes that BCLAF1 fosters glycolysis and tumor progression in ESCC through the YTHDF2-SIX1 pathway in an m6A-specific manner, suggesting a potential target for future therapeutic intervention.
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Affiliation(s)
- Peipei Zhang
- Department of Thoracic Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, China
| | - Weiguang Zhang
- Department of Thoracic Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, China
| | - Xiaoqing Wang
- Department of Thoracic Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, China
| | - Lingling Li
- State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institutes of Biomedical Sciences, Human Phenome Institute, Fudan University, Shanghai, 200433, China
| | - Ye Lin
- Department of Thoracic Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, China
| | - Ningzi Wu
- Department of Thoracic Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, China
| | - Renyan Mao
- Department of Thoracic Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, China
| | - Jihong Lin
- Department of Thoracic Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, China
| | - Mingqiang Kang
- Department of Thoracic Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, China; Department of Cardiothoracic Surgery, Affiliated Hospital of Putian University, Putian, 351100, China; Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, 350108, China.
| | - Chen Ding
- State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institutes of Biomedical Sciences, Human Phenome Institute, Fudan University, Shanghai, 200433, China.
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Relav L, Doghman-Bouguerra M, Ruggiero C, Muzzi JCD, Figueiredo BC, Lalli E. Steroidogenic Factor 1, a Goldilocks Transcription Factor from Adrenocortical Organogenesis to Malignancy. Int J Mol Sci 2023; 24:3585. [PMID: 36835002 PMCID: PMC9959402 DOI: 10.3390/ijms24043585] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 02/02/2023] [Accepted: 02/09/2023] [Indexed: 02/17/2023] Open
Abstract
Steroidogenic factor-1 (SF-1, also termed Ad4BP; NR5A1 in the official nomenclature) is a nuclear receptor transcription factor that plays a crucial role in the regulation of adrenal and gonadal development, function and maintenance. In addition to its classical role in regulating the expression of P450 steroid hydroxylases and other steroidogenic genes, involvement in other key processes such as cell survival/proliferation and cytoskeleton dynamics have also been highlighted for SF-1. SF-1 has a restricted pattern of expression, being expressed along the hypothalamic-pituitary axis and in steroidogenic organs since the time of their establishment. Reduced SF-1 expression affects proper gonadal and adrenal organogenesis and function. On the other hand, SF-1 overexpression is found in adrenocortical carcinoma and represents a prognostic marker for patients' survival. This review is focused on the current knowledge about SF-1 and the crucial importance of its dosage for adrenal gland development and function, from its involvement in adrenal cortex formation to tumorigenesis. Overall, data converge towards SF-1 being a key player in the complex network of transcriptional regulation within the adrenal gland in a dosage-dependent manner.
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Affiliation(s)
- Lauriane Relav
- Institut de Pharmacologie Moleculaire et Cellulaire CNRS UMR 7275, 06560 Valbonne, France
- Universite Cote d’Azur, 06560 Valbonne, France
| | - Mabrouka Doghman-Bouguerra
- Institut de Pharmacologie Moleculaire et Cellulaire CNRS UMR 7275, 06560 Valbonne, France
- Universite Cote d’Azur, 06560 Valbonne, France
| | - Carmen Ruggiero
- Institut de Pharmacologie Moleculaire et Cellulaire CNRS UMR 7275, 06560 Valbonne, France
- Universite Cote d’Azur, 06560 Valbonne, France
| | - João C. D. Muzzi
- Laboratório de Imunoquímica (LIMQ), Pós-Graduação em Microbiologia, Parasitologia e Patologia, Departamento de Patologia Básica, Universidade Federal do Paraná (UFPR), Curitiba 81530-990, PR, Brazil
- Laboratório de Bioinformática e Biologia de Sistemas, Pós-Graduação em Bioinformática, Universidade Federal do Paraná (UFPR), Curitiba 81520-260, PR, Brazil
- Instituto de Pesquisa Pelé Pequeno Príncipe, Oncology Division, Curitiba 80250-060, PR, Brazil
| | - Bonald C. Figueiredo
- Instituto de Pesquisa Pelé Pequeno Príncipe, Oncology Division, Curitiba 80250-060, PR, Brazil
- Centro de Genética Molecular e Pesquisa do Câncer em Crianças (CEGEMPAC), Molecular Oncology Laboratory, Curitiba 80030-110, PR, Brazil
| | - Enzo Lalli
- Institut de Pharmacologie Moleculaire et Cellulaire CNRS UMR 7275, 06560 Valbonne, France
- Universite Cote d’Azur, 06560 Valbonne, France
- Inserm, 06560 Valbonne, France
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Chen HA, Grimshaw AA, Taylor-Giorlando M, Vijayakumar P, Li D, Margetts M, Pelosi E, Vash-Margita A. Ovarian absence: a systematic literature review and case series report. J Ovarian Res 2023; 16:13. [PMID: 36642704 PMCID: PMC9841619 DOI: 10.1186/s13048-022-01090-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Accepted: 12/24/2022] [Indexed: 01/17/2023] Open
Abstract
Ovarian absence is an uncommon condition that most frequently presents unilaterally. Several etiologies for the condition have been proposed, including torsion, vascular accident, and embryological defect. A systematic review was conducted to describe the clinical presentation of ovarian absence, as well as its associations with other congenital anomalies, through a systematic search of Cochrane Library, ClinicalTrials.gov, Google Scholar, Ovid Embase, Ovid Medline, PubMed, Scopus, and Web of Science. Exclusion criteria included cases with suspicion for Differences of Sex Development, lack of surgically-confirmed ovarian absence, and karyotypes other than 46XX. Our search yielded 12,120 citations, of which 79 studies were included. 10 additional studies were found by citation chasing resulting in a total 113 cases including two unpublished cases presented in this review. Abdominal/pelvic pain (30%) and infertility/subfertility (19%) were the most frequent presentations. Ovarian abnormalities were not noted in 28% of cases with pre-operative ovarian imaging results. Approximately 17% of cases had concomitant uterine abnormalities, while 22% had renal abnormalities. Renal abnormalities were more likely in patients with uterine abnormalities (p < 0.005). Torsion or vascular etiology was the most frequently suspected etiology of ovarian absence (52%), followed by indeterminate (27%) and embryologic etiology (21%). Most cases of ovarian absence are likely attributable to torsion or vascular accidents, despite many references to the condition as "agenesis" in the literature. Imaging may fail to correctly diagnose ovarian absence, and diagnostic laparoscopy may be preferable in many cases as genitourinary anatomy and fertility considerations can be assessed during the procedure. Fertility is likely minimally or not affected in women with unilateral ovarian absence.
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Affiliation(s)
| | - Alyssa A Grimshaw
- Yale University, Harvey Cushing/John Hay Whitney Medical Library, New Haven, CT, USA
| | | | - Pavithra Vijayakumar
- Department of Obstetrics and Gynecology, University of Rochester Medical Center, Rochester, NY, USA
| | - Dan Li
- Yale University School of Medicine, New Haven, CT, USA
| | - Miranda Margetts
- Center for American Indian and Rural Health Equity, Montana State University, Bozeman, MT, USA
| | - Emanuele Pelosi
- Centre for Clinical Research, The University of Queensland, Brisbane, QLD, 4072, Australia
| | - Alla Vash-Margita
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale New Haven Hospital, New Haven, CT, USA.
- Yale Department of Obstetrics, Gynecology & Reproductive Medicine, Farnam Memorial Building, 310 Cedar Street, Fl 3, Rm 329, New Haven, CT, 06510, USA.
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7
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Wang L, Yong YL, Wang KK, Xie YX, Qian YC, Zhou FM, Qiu JG, Jiang BH. MKRN2 knockout causes male infertility through decreasing STAT1, SIX4, and TNC expression. Front Endocrinol (Lausanne) 2023; 14:1138096. [PMID: 36967804 PMCID: PMC10036822 DOI: 10.3389/fendo.2023.1138096] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Accepted: 02/24/2023] [Indexed: 03/12/2023] Open
Abstract
Makorin-2 (Mkrn2) is an evolutionarily conserved gene whose biological functions are not fully known. Although recent studies have shed insights on the potential causes of male infertility, its underlining mechanisms still remain to be elucidated. We developed a Mrkn2 knockout mice model to study this gene and found that deletion of Mkrn2 in mice led to male infertility. Interestingly, the expression level of signal transducer and activator of the transcription (STAT)1 was significantly decreased in MKRN2 knockout testis and MEF cells. Co-IP assay showed an interaction between MKRN2 and STAT1. Moreover, our results further indicated that MKRN2 regulated the expression level of SIX4 and tenascin C (TNC) via the EBF transcription factor 2 (EBF2) in mice. The results of our study will provide insights into a new mechanism of male infertility.
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Affiliation(s)
- Lin Wang
- The First Affiliated Hospital of Zhengzhou University, Academy of Medical Science, Zhengzhou University, Zhengzhou, Henan, China
| | - Yan-Ling Yong
- The First Affiliated Hospital of Zhengzhou University, Academy of Medical Science, Zhengzhou University, Zhengzhou, Henan, China
| | - Kun-Kun Wang
- The First Affiliated Hospital of Zhengzhou University, Academy of Medical Science, Zhengzhou University, Zhengzhou, Henan, China
| | - Yun-Xia Xie
- The First Affiliated Hospital of Zhengzhou University, Academy of Medical Science, Zhengzhou University, Zhengzhou, Henan, China
| | - Ying-Chen Qian
- The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Feng-Mei Zhou
- The First Affiliated Hospital of Zhengzhou University, Academy of Medical Science, Zhengzhou University, Zhengzhou, Henan, China
| | - Jian-Ge Qiu
- The First Affiliated Hospital of Zhengzhou University, Academy of Medical Science, Zhengzhou University, Zhengzhou, Henan, China
- *Correspondence: Bing-Hua Jiang, ; Jian-Ge Qiu,
| | - Bing-Hua Jiang
- The First Affiliated Hospital of Zhengzhou University, Academy of Medical Science, Zhengzhou University, Zhengzhou, Henan, China
- *Correspondence: Bing-Hua Jiang, ; Jian-Ge Qiu,
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8
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Transgenic Mouse Models to Study the Development and Maintenance of the Adrenal Cortex. Int J Mol Sci 2022; 23:ijms232214388. [PMID: 36430866 PMCID: PMC9693478 DOI: 10.3390/ijms232214388] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2022] [Revised: 11/09/2022] [Accepted: 11/15/2022] [Indexed: 11/22/2022] Open
Abstract
The cortex of the adrenal gland is organized into concentric zones that produce distinct steroid hormones essential for body homeostasis in mammals. Mechanisms leading to the development, zonation and maintenance of the adrenal cortex are complex and have been studied since the 1800s. However, the advent of genetic manipulation and transgenic mouse models over the past 30 years has revolutionized our understanding of these mechanisms. This review lists and details the distinct Cre recombinase mouse strains available to study the adrenal cortex, and the remarkable progress total and conditional knockout mouse models have enabled us to make in our understanding of the molecular mechanisms regulating the development and maintenance of the adrenal cortex.
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9
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Targeted Disruption of Lats1 and Lats2 in Mice Impairs Testis Development and Alters Somatic Cell Fate. Int J Mol Sci 2022; 23:ijms232113585. [DOI: 10.3390/ijms232113585] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 11/01/2022] [Accepted: 11/02/2022] [Indexed: 11/11/2022] Open
Abstract
Hippo signaling plays an essential role in the development of numerous tissues. Although it was previously shown that the transcriptional effectors of Hippo signaling Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) can fine-tune the regulation of sex differentiation genes in the testes, the role of Hippo signaling in testis development remains largely unknown. To further explore the role of Hippo signaling in the testes, we conditionally deleted the key Hippo kinases large tumor suppressor homolog kinases 1 and -2 (Lats1 and Lats2, two kinases that antagonize YAP and TAZ transcriptional co-regulatory activity) in the somatic cells of the testes using an Nr5a1-cre strain (Lats1flox/flox;Lats2flox/flox;Nr5a1-cre). We report here that early stages of testis somatic cell differentiation were not affected in this model but progressive testis cord dysgenesis was observed starting at gestational day e14.5. Testis cord dysgenesis was further associated with the loss of polarity of the Sertoli cells and the loss of SOX9 expression but not WT1. In parallel with testis cord dysgenesis, a loss of steroidogenic gene expression associated with the appearance of myofibroblast-like cells in the interstitial space was also observed in mutant animals. Furthermore, the loss of YAP phosphorylation, the accumulation of nuclear TAZ (and YAP) in both the Sertoli and interstitial cell populations, and an increase in their transcriptional co-regulatory activity in the testes suggest that the observed phenotype could be attributed at least in part to YAP and TAZ. Taken together, our results suggest that Hippo signaling is required to maintain proper differentiation of testis somatic cells.
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10
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Imaimatsu K, Uchida A, Hiramatsu R, Kanai Y. Gonadal Sex Differentiation and Ovarian Organogenesis along the Cortical-Medullary Axis in Mammals. Int J Mol Sci 2022; 23:13373. [PMID: 36362161 PMCID: PMC9655463 DOI: 10.3390/ijms232113373] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 10/24/2022] [Accepted: 10/31/2022] [Indexed: 09/20/2023] Open
Abstract
In most mammals, the sex of the gonads is based on the fate of the supporting cell lineages, which arises from the proliferation of coelomic epithelium (CE) that surfaces on the bipotential genital ridge in both XY and XX embryos. Recent genetic studies and single-cell transcriptome analyses in mice have revealed the cellular and molecular events in the two-wave proliferation of the CE that produce the supporting cells. This proliferation contributes to the formation of the primary sex cords in the medullary region of both the testis and the ovary at the early phase of gonadal sex differentiation, as well as to that of the secondary sex cords in the cortical region of the ovary at the perinatal stage. To support gametogenesis, the testis forms seminiferous tubules in the medullary region, whereas the ovary forms follicles mainly in the cortical region. The medullary region in the ovary exhibits morphological and functional diversity among mammalian species that ranges from ovary-like to testis-like characteristics. This review focuses on the mechanism of gonadal sex differentiation along the cortical-medullary axis and compares the features of the cortical and medullary regions of the ovary in mammalian species.
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Affiliation(s)
- Kenya Imaimatsu
- Department of Veterinary Anatomy, The University of Tokyo, Bunkyo-ku, Tokyo 113-8654, Japan
| | - Aya Uchida
- Department of Veterinary Anatomy, The University of Tokyo, Bunkyo-ku, Tokyo 113-8654, Japan
- RIKEN BioResouce Research Center, Tsukuba 305-0074, Japan
| | - Ryuji Hiramatsu
- Department of Veterinary Anatomy, The University of Tokyo, Bunkyo-ku, Tokyo 113-8654, Japan
| | - Yoshiakira Kanai
- Department of Veterinary Anatomy, The University of Tokyo, Bunkyo-ku, Tokyo 113-8654, Japan
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11
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Deng D, Xing S, Liu X, Ji Q, Zhai Z, Peng W. Transcriptome analysis of sex-biased gene expression in the spotted-wing Drosophila, Drosophila suzukii (Matsumura). G3 GENES|GENOMES|GENETICS 2022; 12:6588685. [PMID: 35587603 PMCID: PMC9339319 DOI: 10.1093/g3journal/jkac127] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Accepted: 05/11/2022] [Indexed: 11/16/2022]
Abstract
Sexual dimorphism occurs widely throughout insects and has profound influences on evolutionary path. Sex-biased genes are considered to account for most of phenotypic differences between sexes. In order to explore the sex-biased genes potentially associated with sexual dimorphism and sexual development in Drosophila suzukii, a major devastating and invasive crop pest, we conducted whole-organism transcriptome profiling and sex-biased gene expression analysis on adults of both sexes. We identified transcripts of genes involved in several sex-specific physiological and functional processes, including transcripts involved in sex determination, reproduction, olfaction, and innate immune signals. A total of 11,360 differentially expressed genes were identified in the comparison, and 1,957 differentially expressed genes were female-biased and 4,231 differentially expressed genes were male-biased. The pathway predominantly enriched for differentially expressed genes was related to spliceosome, which might reflect the differences in the alternative splicing mechanism between males and females. Twenty-two sex determination and 16 sex-related reproduction genes were identified, and expression pattern analysis revealed that the majority of genes were differentially expressed between sexes. Additionally, the differences in sex-specific olfactory and immune processes were analyzed and the sex-biased expression of these genes may play important roles in pheromone and odor detection, and immune response. As a valuable dataset, our sex-specific transcriptomic data can significantly contribute to the fundamental elucidation of the molecular mechanisms of sexual dimorphism in fruit flies, and may provide candidate genes potentially useful for the development of genetic sexing strains, an important tool for sterile insect technique applications against this economically important species.
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Affiliation(s)
- Dan Deng
- Hunan Provincial Key Laboratory of Animal Intestinal Function and Regulation, State Key Laboratory of Developmental Biology of Freshwater Fish, Hunan International Joint Laboratory of Animal Intestinal Ecology and Health, Hunan Normal University , Changsha 410081, China
| | - Shisi Xing
- Hunan Provincial Key Laboratory of Animal Intestinal Function and Regulation, State Key Laboratory of Developmental Biology of Freshwater Fish, Hunan International Joint Laboratory of Animal Intestinal Ecology and Health, Hunan Normal University , Changsha 410081, China
| | - Xuxiang Liu
- State Key Laboratory of Ecological Pest Control for Fujian and Taiwan Crops, Key Lab of Biopesticide and Chemical Biology, Ministry of Education, Institute of Biological Control, Fujian Agriculture and Forestry University , Fuzhou 350002, China
| | - Qinge Ji
- State Key Laboratory of Ecological Pest Control for Fujian and Taiwan Crops, Key Lab of Biopesticide and Chemical Biology, Ministry of Education, Institute of Biological Control, Fujian Agriculture and Forestry University , Fuzhou 350002, China
| | - Zongzhao Zhai
- Hunan Provincial Key Laboratory of Animal Intestinal Function and Regulation, State Key Laboratory of Developmental Biology of Freshwater Fish, Hunan International Joint Laboratory of Animal Intestinal Ecology and Health, Hunan Normal University , Changsha 410081, China
| | - Wei Peng
- Hunan Provincial Key Laboratory of Animal Intestinal Function and Regulation, State Key Laboratory of Developmental Biology of Freshwater Fish, Hunan International Joint Laboratory of Animal Intestinal Ecology and Health, Hunan Normal University , Changsha 410081, China
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12
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Xie Y, Wu C, Li Z, Wu Z, Hong L. Early Gonadal Development and Sex Determination in Mammal. Int J Mol Sci 2022; 23:ijms23147500. [PMID: 35886859 PMCID: PMC9323860 DOI: 10.3390/ijms23147500] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 06/29/2022] [Accepted: 07/05/2022] [Indexed: 02/04/2023] Open
Abstract
Sex determination is crucial for the transmission of genetic information through generations. In mammal, this process is primarily regulated by an antagonistic network of sex-related genes beginning in embryonic development and continuing throughout life. Nonetheless, abnormal expression of these sex-related genes will lead to reproductive organ and germline abnormalities, resulting in disorders of sex development (DSD) and infertility. On the other hand, it is possible to predetermine the sex of animal offspring by artificially regulating sex-related gene expression, a recent research hotspot. In this paper, we reviewed recent research that has improved our understanding of the mechanisms underlying the development of the gonad and primordial germ cells (PGCs), progenitors of the germline, to provide new directions for the treatment of DSD and infertility, both of which involve manipulating the sex ratio of livestock offspring.
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Affiliation(s)
- Yanshe Xie
- National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou 510630, China; (Y.X.); (C.W.); (Z.L.)
- Guangdong Provincial Key Laboratory of Agro-Animal Genomics and Molecular Breeding, South China Agricultural University, Guangzhou 510630, China
| | - Changhua Wu
- National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou 510630, China; (Y.X.); (C.W.); (Z.L.)
- Guangdong Provincial Key Laboratory of Agro-Animal Genomics and Molecular Breeding, South China Agricultural University, Guangzhou 510630, China
| | - Zicong Li
- National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou 510630, China; (Y.X.); (C.W.); (Z.L.)
- Guangdong Provincial Key Laboratory of Agro-Animal Genomics and Molecular Breeding, South China Agricultural University, Guangzhou 510630, China
| | - Zhenfang Wu
- National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou 510630, China; (Y.X.); (C.W.); (Z.L.)
- Guangdong Provincial Key Laboratory of Agro-Animal Genomics and Molecular Breeding, South China Agricultural University, Guangzhou 510630, China
- Correspondence: (Z.W.); (L.H.)
| | - Linjun Hong
- National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou 510630, China; (Y.X.); (C.W.); (Z.L.)
- Guangdong Provincial Key Laboratory of Agro-Animal Genomics and Molecular Breeding, South China Agricultural University, Guangzhou 510630, China
- Correspondence: (Z.W.); (L.H.)
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13
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Pervasive male-biased expression throughout the germline-specific regions of the sea lamprey genome supports key roles in sex differentiation and spermatogenesis. Commun Biol 2022; 5:434. [PMID: 35538209 PMCID: PMC9090840 DOI: 10.1038/s42003-022-03375-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Accepted: 04/14/2022] [Indexed: 12/13/2022] Open
Abstract
Sea lamprey undergo programmed genome rearrangement (PGR) in which ∼20% of the genome is jettisoned from somatic cells during embryogenesis. Although the role of PGR in embryonic development has been studied, the role of the germline-specific region (GSR) in gonad development is unknown. We analysed RNA-sequence data from 28 sea lamprey gonads sampled across life-history stages, generated a genome-guided de novo superTranscriptome with annotations, and identified germline-specific genes (GSGs). Overall, we identified 638 GSGs that are enriched for reproductive processes and exhibit 36x greater odds of being expressed in testes than ovaries. Next, while 55% of the GSGs have putative somatic paralogs, the somatic paralogs are not differentially expressed between sexes. Further, putative orthologs of some the male-biased GSGs have known functions in sex determination or differentiation in other vertebrates. We conclude that the GSR of sea lamprey plays an important role in testicular differentiation and potentially sex determination. RNA-sequencing of sea lamprey gonads at different life-history stage identifies germline-specific genes which are highly expressed in males during spermatogenesis. This suggests a link between male-biased germline expression and sex differentiation in the sea lamprey.
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14
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Windley SP, Mayère C, McGovern AE, Harvey NL, Nef S, Schwarz Q, Kumar S, Wilhelm D. Loss of NEDD4 causes complete XY gonadal sex reversal in mice. Cell Death Dis 2022; 13:75. [PMID: 35075134 PMCID: PMC8786929 DOI: 10.1038/s41419-022-04519-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 12/16/2021] [Accepted: 01/06/2022] [Indexed: 11/24/2022]
Abstract
Gonadogenesis is the process wherein two morphologically distinct organs, the testis and the ovary, arise from a common precursor. In mammals, maleness is driven by the expression of Sry. SRY subsequently upregulates the related family member Sox9 which is responsible for initiating testis differentiation while repressing factors critical to ovarian development such as FOXL2 and β-catenin. Here, we report a hitherto uncharacterised role for the ubiquitin-protein ligase NEDD4 in this process. XY Nedd4-deficient mice exhibit complete male-to-female gonadal sex reversal shown by the ectopic upregulation of Foxl2 expression at the time of gonadal sex determination as well as insufficient upregulation of Sox9. This sex reversal extends to germ cells with ectopic expression of SYCP3 in XY Nedd4-/- germ cells and significantly higher Sycp3 transcripts in XY and XX Nedd4-deficient mice when compared to both XY and XX controls. Further, Nedd4-/- mice exhibit reduced gonadal precursor cell formation and gonadal size as a result of reduced proliferation within the developing gonad as well as reduced Nr5a1 expression. Together, these results establish an essential role for NEDD4 in XY gonadal sex determination and development and suggest a potential role for NEDD4 in orchestrating these cell fate decisions through the suppression of the female pathway to ensure proper testis differentiation.
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Affiliation(s)
- Simon P Windley
- Department of Anatomy & Physiology, The University of Melbourne, Parkville, 3010, Australia
| | - Chloé Mayère
- Department of Genetic Medicine and Development, University of Geneva, 1211, Geneva, Switzerland
| | - Alice E McGovern
- Department of Anatomy & Physiology, The University of Melbourne, Parkville, 3010, Australia
| | - Natasha L Harvey
- Centre for Cancer Biology, University of South Australia, Adelaide, 5001, Australia
| | - Serge Nef
- Department of Genetic Medicine and Development, University of Geneva, 1211, Geneva, Switzerland
| | - Quenten Schwarz
- Centre for Cancer Biology, University of South Australia, Adelaide, 5001, Australia
| | - Sharad Kumar
- Centre for Cancer Biology, University of South Australia, Adelaide, 5001, Australia
| | - Dagmar Wilhelm
- Department of Anatomy & Physiology, The University of Melbourne, Parkville, 3010, Australia.
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15
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Rafiq A, Aashaq S, Jan I, Beigh MA. SIX1 transcription factor: A review of cellular functions and regulatory dynamics. Int J Biol Macromol 2021; 193:1151-1164. [PMID: 34742853 DOI: 10.1016/j.ijbiomac.2021.10.133] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 10/17/2021] [Accepted: 10/18/2021] [Indexed: 10/19/2022]
Abstract
Sine Oculis Homeobox 1 (SIX1) is a member of homeobox transcription factor family having pivotal roles in organismal development and differentiation. This protein functionally acts to regulate the expression of different proteins that are involved in organ development during embryogenesis and in disorders like cancer. Aberrant expression of this homeoprotein has therefore been reported in multiple pathological complexities like hearing impairment and renal anomalies during development and tumorigenesis in adult life. Most of the cellular effects mediated by it are mostly due to its role as a transcription factor. This review presents a concise narrative of its structure, interaction partners and cellular functions vis a vis its role in cancer. We thoroughly discuss the reported molecular mechanisms that govern its function in cellular milieu. Its post-translational regulation by phosphorylation and ubiquitination are also discussed with an emphasis on yet to be explored mechanistic insights regulating its molecular dynamics to fully comprehend its role in development and disease.
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Affiliation(s)
- Asma Rafiq
- Department of Nanotechnology, University of Kashmir, Hazratbal Campus, Srinagar JK-190006, India
| | - Sabreena Aashaq
- Department of Immunology and Molecular Medicine, Sher-i-Kashmir Institute of Medical Sciences, Soura, Srinagar JK-190011, India
| | - Iqra Jan
- Department of Nanotechnology, University of Kashmir, Hazratbal Campus, Srinagar JK-190006, India
| | - Mushtaq A Beigh
- Department of Nanotechnology, University of Kashmir, Hazratbal Campus, Srinagar JK-190006, India.
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16
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Abou Nader N, Boyer A. Adrenal Cortex Development and Maintenance: Knowledge Acquired From Mouse Models. Endocrinology 2021; 162:6362524. [PMID: 34473283 DOI: 10.1210/endocr/bqab187] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Indexed: 11/19/2022]
Abstract
The adrenal cortex is an endocrine organ organized into concentric zones that are specialized to produce specific steroid hormones essential for life. The development and maintenance of the adrenal cortex are complex, as a fetal adrenal is first formed from a common primordium with the gonads, followed by its separation in a distinct primordium, the invasion of the adrenal primordium by neural crest-derived cells to form the medulla, and finally its encapsulation. The fetal cortex is then replaced by a definitive cortex, which will establish zonation and be maintained throughout life by regeneration relying on the proliferation, centripetal migration, and differentiation of several stem/progenitor cell populations whose activities are sex-specific. Here, we highlight the advances made, using transgenic mouse models, to delineate the molecular mechanisms regulating these processes.
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Affiliation(s)
- Nour Abou Nader
- Centre de Recherche en Reproduction et Fertilité, Faculté de Médecine Vétérinaire, Université de Montréal, Saint-Hyacinthe, Canada
| | - Alexandre Boyer
- Centre de Recherche en Reproduction et Fertilité, Faculté de Médecine Vétérinaire, Université de Montréal, Saint-Hyacinthe, Canada
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17
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Okashita N, Tachibana M. Transcriptional Regulation of the Y-Linked Mammalian Testis-Determining Gene SRY. Sex Dev 2021; 15:351-359. [PMID: 34583357 DOI: 10.1159/000519217] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Accepted: 07/12/2021] [Indexed: 11/19/2022] Open
Abstract
Mammalian male sex differentiation is triggered during embryogenesis by the activation of the Y-linked testis-determining gene SRY. Since insufficient or delayed expression of SRY results in XY gonadal sex reversal, accurate regulation of SRY is critical for male development in XY animals. In humans, dysregulation of SRY may cause disorders of sex development. Mouse Sry is the most intensively studied mammalian model of sex determination. Sry expression is controlled in a spatially and temporally stringent manner. Several transcription factors play a key role in sex determination as trans-acting factors for Sry expression. In addition, recent studies have shown that several epigenetic modifications of Sry are involved in sex determination as cis-acting factors for Sry expression. Herein, we review the current understanding of transcription factor- and epigenetic modifier-mediated regulation of SRY/Sry expression.
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Affiliation(s)
- Naoki Okashita
- Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan
| | - Makoto Tachibana
- Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan
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18
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Meurer L, Ferdman L, Belcher B, Camarata T. The SIX Family of Transcription Factors: Common Themes Integrating Developmental and Cancer Biology. Front Cell Dev Biol 2021; 9:707854. [PMID: 34490256 PMCID: PMC8417317 DOI: 10.3389/fcell.2021.707854] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Accepted: 06/28/2021] [Indexed: 01/19/2023] Open
Abstract
The sine oculis (SIX) family of transcription factors are key regulators of developmental processes during embryogenesis. Members of this family control gene expression to promote self-renewal of progenitor cell populations and govern mechanisms of cell differentiation. When the function of SIX genes becomes disrupted, distinct congenital defects develops both in animal models and humans. In addition to the embryonic setting, members of the SIX family have been found to be critical regulators of tumorigenesis, promoting cell proliferation, epithelial-to-mesenchymal transition, and metastasis. Research in both the fields of developmental biology and cancer research have provided an extensive understanding of SIX family transcription factor functions. Here we review recent progress in elucidating the role of SIX family genes in congenital disease as well as in the promotion of cancer. Common themes arise when comparing SIX transcription factor function during embryonic and cancer development. We highlight the complementary nature of these two fields and how knowledge in one area can open new aspects of experimentation in the other.
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Affiliation(s)
- Logan Meurer
- Department of Basic Sciences, NYIT College of Osteopathic Medicine at Arkansas State University, Jonesboro, AR, United States
| | - Leonard Ferdman
- Department of Basic Sciences, NYIT College of Osteopathic Medicine at Arkansas State University, Jonesboro, AR, United States
| | - Beau Belcher
- Department of Biological Sciences, Arkansas State University, Jonesboro, AR, United States
| | - Troy Camarata
- Department of Basic Sciences, NYIT College of Osteopathic Medicine at Arkansas State University, Jonesboro, AR, United States
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19
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Estermann MA, Hirst CE, Major AT, Smith CA. The homeobox gene TGIF1 is required for chicken ovarian cortical development and generation of the juxtacortical medulla. Development 2021; 148:dev199646. [PMID: 34387307 PMCID: PMC8406534 DOI: 10.1242/dev.199646] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Accepted: 07/13/2021] [Indexed: 12/12/2022]
Abstract
During early embryogenesis in amniotic vertebrates, the gonads differentiate into either ovaries or testes. The first cell lineage to differentiate gives rise to the supporting cells: Sertoli cells in males and pre-granulosa cells in females. These key cell types direct the differentiation of the other cell types in the gonad, including steroidogenic cells. The gonadal surface epithelium and the interstitial cell populations are less well studied, and little is known about their sexual differentiation programs. Here, we show the requirement of the homeobox transcription factor gene TGIF1 for ovarian development in the chicken embryo. TGIF1 is expressed in the two principal ovarian somatic cell populations: the cortex and the pre-granulosa cells of the medulla. TGIF1 expression is associated with an ovarian phenotype in estrogen-mediated sex reversal experiments. Targeted misexpression and gene knockdown indicate that TGIF1 is required, but not sufficient, for proper ovarian cortex formation. In addition, TGIF1 is identified as the first known regulator of juxtacortical medulla development. These findings provide new insights into chicken ovarian differentiation and development, specifically cortical and juxtacortical medulla formation.
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Affiliation(s)
| | | | | | - Craig Allen Smith
- Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton VIC 3800, Australia
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20
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Characteristics and possible mechanisms of 46, XY differences in sex development caused by novel compound variants in NR5A1 and MAP3K1. Orphanet J Rare Dis 2021; 16:268. [PMID: 34112222 PMCID: PMC8194036 DOI: 10.1186/s13023-021-01908-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Accepted: 06/07/2021] [Indexed: 02/08/2023] Open
Abstract
Background Dozens of genes are involved in 46, XY differences in sex development (DSD). Notably, about 3/4 of patients cannot make a clear etiology diagnosis and single gene variant identified cannot fully explain the clinical heterogeneity of 46, XY DSD. Materials and methods We conducted a systematic clinical analysis of a 46, XY DSD patient, and applied whole-exome sequencing for the genetic analysis of this pedigree. The identified variants were analyzed by bioinformatic analysis and in vitro studies were performed in human embryonic kidney 293T (HEK-293T) cells which were transiently transfected with wild type or variant NR5A1 and MAP3K1 plasmid. Furthermore, protein production of SRY-box transcription factor 9 (SOX9) was analyzed in cell lysates. Results A novel NR5A1 variant (c.929A > C, p. His310Pro) and a rare MAP3K1 variant (c.2282T > C, p. Ile761Thr) were identified in the proband, whereas the proband's mother and sister who only carry rare MAP3K1 variant have remained phenotypically healthy to the present. These two variants were predicted to be pathogenic by bioinformatic analysis. In vitro, NR5A1 variant decreased the SOX9 production by 82.11% compared to wild type NR5A1, while MAP3K1 variant had little effect on the SOX9 production compared to wild type MAP3K1. Compared to wild type NR5A1 transfection, the SOX9 production of cells transfected with both wild type plasmids decreased by about 17.40%. Compared to variant NR5A1 transfection, the SOX9 production of cells transfected with both variant plasmids increased by the 36.64%. Conclusions Our findings suggested the novel compound variants of NR5A1 and MAP3K1 can alter the expression of SOX9 and ultimately lead to abnormality of sex development. Supplementary Information The online version contains supplementary material available at 10.1186/s13023-021-01908-z.
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21
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Camolotto SA, Belova VK, Torre-Healy L, Vahrenkamp JM, Berrett KC, Conway H, Shea J, Stubben C, Moffitt R, Gertz J, Snyder EL. Reciprocal regulation of pancreatic ductal adenocarcinoma growth and molecular subtype by HNF4α and SIX1/4. Gut 2021; 70:900-914. [PMID: 32826305 PMCID: PMC7945295 DOI: 10.1136/gutjnl-2020-321316] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Revised: 06/17/2020] [Accepted: 06/30/2020] [Indexed: 12/13/2022]
Abstract
OBJECTIVE Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a 5-year survival of less than 5%. Transcriptomic analysis has identified two clinically relevant molecular subtypes of PDAC: classical and basal-like. The classical subtype is characterised by a more favourable prognosis and better response to chemotherapy than the basal-like subtype. The classical subtype also expresses higher levels of lineage specifiers that regulate endodermal differentiation, including the nuclear receptor hepatocyte nuclear factor 4 α (HNF4α). The objective of this study is to evaluate the role of HNF4α, SIX4 and SIX1 in regulating the growth and molecular subtype of PDAC. DESIGN We manipulate the expression of HNF4α, SIX4 and SIX1 in multiple in vitro and in vivo PDAC models. We determine the consequences of manipulating these genes on PDAC growth, differentiation and molecular subtype using functional assays, gene expression analysis and cross-species comparisons with human datasets. RESULTS We show that HNF4α restrains tumour growth and drives tumour cells toward an epithelial identity. Gene expression analysis of murine models and human tumours shows that HNF4α activates expression of genes associated with the classical subtype. HNF4α also directly represses SIX4 and SIX1, two mesodermal/neuronal lineage specifiers expressed in the basal-like subtype. Finally, SIX4 and SIX1 drive proliferation and regulate differentiation in HNF4α-negative PDAC. CONCLUSION Our data show that HNF4α regulates the growth and molecular subtype of PDAC by multiple mechanisms, including activation of the classical gene expression programme and repression of SIX4 and SIX1, which may represent novel dependencies of the basal-like subtype.
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Affiliation(s)
- Soledad A Camolotto
- Department of Pathology, Huntsman Cancer Institute, University of Utah Health, Salt Lake City, Utah, USA
| | - Veronika K Belova
- Department of Pathology, Huntsman Cancer Institute, University of Utah Health, Salt Lake City, Utah, USA
| | - Luke Torre-Healy
- Department of Biomedical Informatics, Stony Brook University, Stony Brook, New York, USA
| | - Jeffery M Vahrenkamp
- Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah Health, Salt Lake City, Utah, USA
| | - Kristofer C Berrett
- Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah Health, Salt Lake City, Utah, USA
| | - Hannah Conway
- HCI Clinical Trials Operations, Huntsman Cancer Institute, University of Utah Health, Salt Lake City, Utah, USA
| | - Jill Shea
- Department of Surgery, University of Utah, Salt Lake City, Utah, USA
| | - Chris Stubben
- Bioinformatics Shared Resource, Huntsman Cancer Institute, University of Utah Health, Salt Lake City, Utah, USA
| | - Richard Moffitt
- Department of Biomedical Informatics, Stony Brook University, Stony Brook, New York, USA
| | - Jason Gertz
- Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah Health, Salt Lake City, Utah, USA
| | - Eric L Snyder
- Department of Pathology, Huntsman Cancer Institute, University of Utah Health, Salt Lake City, Utah, USA
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22
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Sasaki K, Oguchi A, Cheng K, Murakawa Y, Okamoto I, Ohta H, Yabuta Y, Iwatani C, Tsuchiya H, Yamamoto T, Seita Y, Saitou M. The embryonic ontogeny of the gonadal somatic cells in mice and monkeys. Cell Rep 2021; 35:109075. [PMID: 33951437 DOI: 10.1016/j.celrep.2021.109075] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Revised: 01/21/2021] [Accepted: 04/12/2021] [Indexed: 12/31/2022] Open
Abstract
In the early fetal stage, the gonads are bipotent and only later become the ovary or testis, depending on the genetic sex. Despite many studies examining how sex determination occurs from biopotential gonads, the spatial and temporal organization of bipotential gonads and their progenitors is poorly understood. Here, using lineage tracing in mice, we find that the gonads originate from a T+ primitive streak through WT1+ posterior intermediate mesoderm and appear to share origins anteriorly with the adrenal glands and posteriorly with the metanephric mesenchyme. Comparative single-cell transcriptomic analyses in mouse and cynomolgus monkey embryos reveal the convergence of the lineage trajectory and genetic programs accompanying the specification of biopotential gonadal progenitor cells. This process involves sustained expression of epithelial genes and upregulation of mesenchymal genes, thereby conferring an epithelial-mesenchymal hybrid state. Our study provides key resources for understanding early gonadogenesis in mice and primates.
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Affiliation(s)
- Kotaro Sasaki
- Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
| | - Akiko Oguchi
- RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa 230-0045, Japan; Institute for the Advanced Study of Human Biology (ASHBi), Kyoto University, Kyoto 606-8501, Japan
| | - Keren Cheng
- Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Yasuhiro Murakawa
- RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa 230-0045, Japan; Institute for the Advanced Study of Human Biology (ASHBi), Kyoto University, Kyoto 606-8501, Japan
| | - Ikuhiro Okamoto
- Institute for the Advanced Study of Human Biology (ASHBi), Kyoto University, Kyoto 606-8501, Japan; Department of Anatomy and Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan
| | - Hiroshi Ohta
- Institute for the Advanced Study of Human Biology (ASHBi), Kyoto University, Kyoto 606-8501, Japan; Department of Anatomy and Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan
| | - Yukihiro Yabuta
- Institute for the Advanced Study of Human Biology (ASHBi), Kyoto University, Kyoto 606-8501, Japan; Department of Anatomy and Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan
| | - Chizuru Iwatani
- Research Center for Animal Life Science, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan
| | - Hideaki Tsuchiya
- Research Center for Animal Life Science, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan
| | - Takuya Yamamoto
- Institute for the Advanced Study of Human Biology (ASHBi), Kyoto University, Kyoto 606-8501, Japan; Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan; AMED-CREST, AMED, Tokyo 100-0004, Japan; Medical-risk Avoidance based on iPS Cells Team, RIKEN Center for Advanced Intelligence Project (AIP), Kyoto 606-8507, Japan
| | - Yasunari Seita
- Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Bell Research Center for Reproductive Health and Cancer, Nagoya 460-0003, Japan
| | - Mitinori Saitou
- Institute for the Advanced Study of Human Biology (ASHBi), Kyoto University, Kyoto 606-8501, Japan; Department of Anatomy and Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan; Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.
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23
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Oikonomakos I, Weerasinghe Arachchige LC, Schedl A. Developmental mechanisms of adrenal cortex formation and their links with adult progenitor populations. Mol Cell Endocrinol 2021; 524:111172. [PMID: 33484742 DOI: 10.1016/j.mce.2021.111172] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Revised: 12/15/2020] [Accepted: 01/13/2021] [Indexed: 12/16/2022]
Abstract
The adrenal cortex is the main steroid producing organ of the human body. Studies on adrenal tissue renewal have been neglected for many years, but recent intensified research has seen tremendous progress in our understanding of the formation and homeostasis of this organ. However, cell turnover of the adrenal cortex appears to be complex and several cell populations have been identified that can differentiate into steroidogenic cells and contribute to adrenal cortex renewal. The purpose of this review is to provide an overview of how the adrenal cortex develops and how stem cell populations relate to its developmental progenitors. Finally, we will summarize present and future approaches to harvest the potential of progenitor/stem cells for future cell replacement therapies.
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Affiliation(s)
- Ioannis Oikonomakos
- Université Côte d'Azur, Inserm, CNRS, Institut de Biologie Valrose, 06108, Nice, France.
| | | | - Andreas Schedl
- Université Côte d'Azur, Inserm, CNRS, Institut de Biologie Valrose, 06108, Nice, France.
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Luo BY, Xiong XY, Liu X, He XY, Qiu GF. Identification and characterization of sex-biased and differentially expressed miRNAs in gonadal developments of the Chinese mitten crab, Eriocheir sinensis. Mol Reprod Dev 2021; 88:217-227. [PMID: 33655621 DOI: 10.1002/mrd.23459] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2020] [Revised: 12/25/2020] [Accepted: 02/02/2021] [Indexed: 01/02/2023]
Abstract
MicroRNA (miRNA) is a posttranscriptional downregulator that plays a vital role in a wide variety of biological processes. In this study, we constructed five ovarian and testicular small RNA libraries using two somatic libraries as reference controls for the identification of sex-biased miRNAs and gonadal differentially expressed miRNAs (DEMs) of the Chinese mitten crab, Eriocheir sinensis. A total of 535 known and 243 novel miRNAs were identified, including 312 sex-biased miRNAs and 402 gonadal DEMs. KEGG pathway analysis showed that DEM target genes were statistically enriched in MAPK, Wnt, and GnRH signaling pathway, and so on. A number of the sex-biased miRNAs target genes associated with sex determination/differentiation, such as IAG, Dsx, Dmrt1, and Fem1, while others target the genes related to gonadal development, such as P450s, Wnt, Ef1, and Tra-2c. Dual-luciferase reporter assay in vitro further confirmed that miR-34 and let-7b can downregulate IAG expression, miR-9-5p, let-7d, let-7b, and miR-8915 can downregulate Dsx. Taken together, these data strongly suggest a potential role for the sex-biased miRNAs in sex determination/differentiation and gonadal development in the crab.
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Affiliation(s)
- Bi-Yun Luo
- National Demonstration Center for Experimental Fisheries Science Education, Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Ministry of Education, Key Laboratory of Freshwater Aquatic Genetic Resources, Ministry of Agriculture, Shanghai Engineering Research Center of Aquaculture, Shanghai Ocean University, Shanghai, China
| | - Xin-Yi Xiong
- National Demonstration Center for Experimental Fisheries Science Education, Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Ministry of Education, Key Laboratory of Freshwater Aquatic Genetic Resources, Ministry of Agriculture, Shanghai Engineering Research Center of Aquaculture, Shanghai Ocean University, Shanghai, China
| | - Xue Liu
- National Demonstration Center for Experimental Fisheries Science Education, Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Ministry of Education, Key Laboratory of Freshwater Aquatic Genetic Resources, Ministry of Agriculture, Shanghai Engineering Research Center of Aquaculture, Shanghai Ocean University, Shanghai, China
| | - Xue-Ying He
- National Demonstration Center for Experimental Fisheries Science Education, Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Ministry of Education, Key Laboratory of Freshwater Aquatic Genetic Resources, Ministry of Agriculture, Shanghai Engineering Research Center of Aquaculture, Shanghai Ocean University, Shanghai, China
| | - Gao-Feng Qiu
- National Demonstration Center for Experimental Fisheries Science Education, Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Ministry of Education, Key Laboratory of Freshwater Aquatic Genetic Resources, Ministry of Agriculture, Shanghai Engineering Research Center of Aquaculture, Shanghai Ocean University, Shanghai, China
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25
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Yan YL, Titus T, Desvignes T, BreMiller R, Batzel P, Sydes J, Farnsworth D, Dillon D, Wegner J, Phillips JB, Peirce J, Dowd J, Undiagnosed Diseases Network, Buck CL, Miller A, Westerfield M, Postlethwait JH. A fish with no sex: gonadal and adrenal functions partition between zebrafish NR5A1 co-orthologs. Genetics 2021; 217:iyaa030. [PMID: 33724412 PMCID: PMC8045690 DOI: 10.1093/genetics/iyaa030] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Accepted: 11/16/2020] [Indexed: 02/06/2023] Open
Abstract
People with NR5A1 mutations experience testicular dysgenesis, ovotestes, or adrenal insufficiency, but we do not completely understand the origin of this phenotypic diversity. NR5A1 is expressed in gonadal soma precursor cells before expression of the sex-determining gene SRY. Many fish have two co-orthologs of NR5A1 that likely partitioned ancestral gene subfunctions between them. To explore ancestral roles of NR5A1, we knocked out nr5a1a and nr5a1b in zebrafish. Single-cell RNA-seq identified nr5a1a-expressing cells that co-expressed genes for steroid biosynthesis and the chemokine receptor Cxcl12a in 1-day postfertilization (dpf) embryos, as does the mammalian adrenal-gonadal (interrenal-gonadal) primordium. In 2dpf embryos, nr5a1a was expressed stronger in the interrenal-gonadal primordium than in the early hypothalamus but nr5a1b showed the reverse. Adult Leydig cells expressed both ohnologs and granulosa cells expressed nr5a1a stronger than nr5a1b. Mutants for nr5a1a lacked the interrenal, formed incompletely differentiated testes, had no Leydig cells, and grew far larger than normal fish. Mutants for nr5a1b formed a disorganized interrenal and their gonads completely disappeared. All homozygous mutant genotypes lacked secondary sex characteristics, including male breeding tubercles and female sex papillae, and had exceedingly low levels of estradiol, 11-ketotestosterone, and cortisol. RNA-seq showed that at 21dpf, some animals were developing as females and others were not, independent of nr5a1 genotype. By 35dpf, all mutant genotypes greatly under-expressed ovary-biased genes. Because adult nr5a1a mutants form gonads but lack an interrenal and conversely, adult nr5a1b mutants lack a gonad but have an interrenal, the adrenal, and gonadal functions of the ancestral nr5a1 gene partitioned between ohnologs after the teleost genome duplication, likely owing to reciprocal loss of ancestral tissue-specific regulatory elements. Identifying such elements could provide hints to otherwise unexplained cases of Differences in Sex Development.
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Affiliation(s)
- Yi-Lin Yan
- Institute of Neuroscience, University of Oregon, Eugene, OR 97403, USA
| | - Tom Titus
- Institute of Neuroscience, University of Oregon, Eugene, OR 97403, USA
| | - Thomas Desvignes
- Institute of Neuroscience, University of Oregon, Eugene, OR 97403, USA
| | - Ruth BreMiller
- Institute of Neuroscience, University of Oregon, Eugene, OR 97403, USA
| | - Peter Batzel
- Institute of Neuroscience, University of Oregon, Eugene, OR 97403, USA
| | - Jason Sydes
- Institute of Neuroscience, University of Oregon, Eugene, OR 97403, USA
| | - Dylan Farnsworth
- Institute of Neuroscience, University of Oregon, Eugene, OR 97403, USA
| | - Danielle Dillon
- Department of Biological Sciences, Northern Arizona University, Flagstaff, AZ 86011, USA
| | - Jeremy Wegner
- Institute of Neuroscience, University of Oregon, Eugene, OR 97403, USA
| | | | - Judy Peirce
- Institute of Neuroscience, University of Oregon, Eugene, OR 97403, USA
| | - John Dowd
- Institute of Neuroscience, University of Oregon, Eugene, OR 97403, USA
| | | | - Charles Loren Buck
- Department of Biological Sciences, Northern Arizona University, Flagstaff, AZ 86011, USA
| | - Adam Miller
- Institute of Neuroscience, University of Oregon, Eugene, OR 97403, USA
| | - Monte Westerfield
- Institute of Neuroscience, University of Oregon, Eugene, OR 97403, USA
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26
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Xu C, Mohsin A, Luo Y, Xie L, Peng Y, Wang Q, Ahmed W, Hang H, Zhuang Y, Guo M. Inducing Non-genetically Modified Induced Embryonic Sertoli Cells Derived From Embryonic Stem Cells With Recombinant Protein Factors. Front Cell Dev Biol 2021; 8:533543. [PMID: 33585437 PMCID: PMC7875124 DOI: 10.3389/fcell.2020.533543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Accepted: 08/13/2020] [Indexed: 11/19/2022] Open
Abstract
Embryonic Sertoli cells (eSCs) possess multiple supporting functions and research value in gonadal development and sex determination. However, the limitation of acquiring quality eSCs had hindered the further application. Herein, we successfully derived non-genetically modified (non-GM)-induced embryonic Sertoli-like cells (eSLCs) from mouse embryonic stem cells (ESCs) with a TM4 cell-derived conditioned medium containing recombinant endogenous protein factors Sry, Sox9, Sf1, Wt1, Gata4, and Dmrt1. These eSLCs were determined through morphology; transcriptional expression levels of stage-specific, epithelial, and mesenchymal marker genes; flow cytometry, immunofluorescence; and immunocytochemistry and functionally determined by coculture with spermatogonia stem cells. Results indicated that these eSLCs performed similarly to eSCs in specific biomarkers and expression of marker genes and supported the maturation of spermatogonia. The study induced eSLCs from mouse ESCs by defined protein factors. However, the inducing efficiency of the non-GM method was still lower than that of the lentiviral transduction method. Thus, this work established a foundation for future production of non-GM eSLCs for clinical applications and fundamental theory research.
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Affiliation(s)
- Chenze Xu
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, China
| | - Ali Mohsin
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, China
| | - Yanxia Luo
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, China
| | - Lili Xie
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, China
| | - Yan Peng
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, China
| | - Qizheng Wang
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, China
| | - Waqas Ahmed
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, China
| | - Haifeng Hang
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, China.,Engineering Research Centre of Processes System, Ministry of Education, East China University of Science and Technology, Shanghai, China
| | - Yingping Zhuang
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, China.,Engineering Research Centre of Processes System, Ministry of Education, East China University of Science and Technology, Shanghai, China
| | - Meijin Guo
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, China.,Engineering Research Centre of Processes System, Ministry of Education, East China University of Science and Technology, Shanghai, China.,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
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27
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Li Y, Jiang X, Yan X, Wang Y. Upregulation of SIX4 indicates poor clinical outcome and promotes tumor growth and cell metastasis in esophageal squamous cell carcinoma. Thorac Cancer 2021; 12:752-759. [PMID: 33481352 PMCID: PMC7952808 DOI: 10.1111/1759-7714.13832] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Revised: 12/23/2020] [Accepted: 12/24/2020] [Indexed: 12/24/2022] Open
Abstract
Background The role of sine oculis homeobox 4 (SIX4) has been found in some malignant tumors. However, there have been few studies on the function of SIX4 in esophageal squamous cell carcinoma (ESCC). This study aimed to explore the regulatory mechanism of SIX4 in ESCC. Methods RT‐qPCR and Western blot analysis were used to measure mRNA and protein expression. The function of SIX4 was investigated using CCK‐8, colony formation, flow cytometry, wound healing and transwell assays. A mouse xenograft tumor assay was designed to perform in vivo experiments. Results SIX4 was upregulated in ESCC and indicated poor clinical outcomes in ESCC patients. Functionally, knockdown of SIX4 inhibited cell proliferation and induced apoptosis in ESCC. In addition, the silencing of SIX4 inhibited cell migration, invasion and EMT in ESCC. More importantly, upregulation of SIX4 could activate the PI3K/AKT pathway in ESCC cells and promote tumor growth in vivo. Conclusions Upregulation of SIX4 indicates poor clinical outcomes in ESCC patients and promotes tumor growth and cell metastasis in ESCC.
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Affiliation(s)
- Yanping Li
- Department of Gastroenterology, Rizhao Hospital of TCM, Rizhao, China
| | - Xiaomei Jiang
- Outpatient Department, Qingdao Eighth People's Hospital, Qingdao, China
| | - Xiaoyan Yan
- Health Management Department, Qingdao Eighth People's Hospital, Qingdao, China
| | - Yanzheng Wang
- Department of Clinical Laboratory, Yantaishan Hospital, Yantai, China
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28
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Yang S, Han H, Li J, Zhang Y, Zhao J, Wei H, Hasi T, Lv H, Zhao X, Quan K. Transcriptomic analysis of gene expression in normal goat ovary and intersex goat gonad. Reprod Domest Anim 2020; 56:12-25. [PMID: 33073450 DOI: 10.1111/rda.13844] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Accepted: 10/14/2020] [Indexed: 01/21/2023]
Abstract
Intersexuality is a congenital reproductive disorder that usually occurs in hornless goats, hindering breeding of goats with hornless traits and the development of the goat industry. In this study, we aimed to identify differentially expressed genes in intersex and normal goat gonads by comparing gene transcription profiles of intersex and normal goat gonads. As intersex goats are genetically based on females, we chose female goats as controls. The goats in the control group and the experimental group were both over one-year old. We evaluated the anatomical characteristics of the reproductive organs of five intersex goats using histopathological methods. The gonads were found to be ovarian and testicular types. RNA-Seq technology was used to identify differentially expressed genes in gonads and normal goat ovary tissues. Transcription analysis results were verified by qPCR. The results showed that 2,748 DEGs were upregulated and 3,327 DEGs were downregulated in intersex ovaries unlike in controls, whereas 2006 DEGs were upregulated and 2032 DEGs were downregulated in the interstitial testes. Many of these genes play important roles in mammalian sex determination and sex differentiation, such as SOX9, WT1, GATA4, DMRT1, DHH, AMH, CYP19A1 and FST. We found that many DEGs are involved in biological developmental regulation by GO and KEGG enrichment analyses, and that most genes associated with the steroid synthesis pathway were downregulated. The DEGs identified in this study may be involved in the regulation of intersex goat sex determination and differentiation, and may increase our understanding of the molecular mechanisms of mammalian sex differentiation.
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Affiliation(s)
- Shuai Yang
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou, China
| | - Haoyuan Han
- College of Animal Science and Technology, Henan University of Animal Husbandry and Economy, Zhengzhou, China
| | - Jun Li
- College of Animal Science and Technology, Henan University of Animal Husbandry and Economy, Zhengzhou, China
| | - Yong Zhang
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou, China
| | - JinYan Zhao
- College of Animal Science and Technology, Henan University of Animal Husbandry and Economy, Zhengzhou, China
| | - Hongfang Wei
- College of Animal Science and Technology, Henan University of Animal Husbandry and Economy, Zhengzhou, China
| | - Tonglaga Hasi
- College of Animal Science and Technology, Henan University of Animal Husbandry and Economy, Zhengzhou, China
| | - Huifang Lv
- College of Animal Science and Technology, Henan University of Animal Husbandry and Economy, Zhengzhou, China
| | - Xingxu Zhao
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou, China
| | - Kai Quan
- College of Animal Science and Technology, Henan University of Animal Husbandry and Economy, Zhengzhou, China
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29
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Nagahama Y, Chakraborty T, Paul-Prasanth B, Ohta K, Nakamura M. Sex determination, gonadal sex differentiation, and plasticity in vertebrate species. Physiol Rev 2020; 101:1237-1308. [PMID: 33180655 DOI: 10.1152/physrev.00044.2019] [Citation(s) in RCA: 141] [Impact Index Per Article: 28.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
A diverse array of sex determination (SD) mechanisms, encompassing environmental to genetic, have been found to exist among vertebrates, covering a spectrum from fixed SD mechanisms (mammals) to functional sex change in fishes (sequential hermaphroditic fishes). A major landmark in vertebrate SD was the discovery of the SRY gene in 1990. Since that time, many attempts to clone an SRY ortholog from nonmammalian vertebrates remained unsuccessful, until 2002, when DMY/dmrt1by was discovered as the SD gene of a small fish, medaka. Surprisingly, however, DMY/dmrt1by was found in only 2 species among more than 20 species of medaka, suggesting a large diversity of SD genes among vertebrates. Considerable progress has been made over the last 3 decades, such that it is now possible to formulate reasonable paradigms of how SD and gonadal sex differentiation may work in some model vertebrate species. This review outlines our current understanding of vertebrate SD and gonadal sex differentiation, with a focus on the molecular and cellular mechanisms involved. An impressive number of genes and factors have been discovered that play important roles in testicular and ovarian differentiation. An antagonism between the male and female pathway genes exists in gonads during both sex differentiation and, surprisingly, even as adults, suggesting that, in addition to sex-changing fishes, gonochoristic vertebrates including mice maintain some degree of gonadal sexual plasticity into adulthood. Importantly, a review of various SD mechanisms among vertebrates suggests that this is the ideal biological event that can make us understand the evolutionary conundrums underlying speciation and species diversity.
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Affiliation(s)
- Yoshitaka Nagahama
- Laboratory of Reproductive Biology, National Institute for Basic Biology, Okazaki, Japan.,South Ehime Fisheries Research Center, Ehime University, Ainan, Japan.,Faculty of Biological Science and Technology, Kanazawa University, Ishikawa, Japan
| | - Tapas Chakraborty
- Laboratory of Reproductive Biology, National Institute for Basic Biology, Okazaki, Japan.,South Ehime Fisheries Research Center, Ehime University, Ainan, Japan.,Laboratory of Marine Biology, Faculty of Agriculture, Kyushu University, Fukouka, Japan.,Karatsu Satellite of Aqua-Bioresource Innovation Center, Kyushu University, Karatsu, Japan
| | - Bindhu Paul-Prasanth
- Laboratory of Reproductive Biology, National Institute for Basic Biology, Okazaki, Japan.,Centre for Nanosciences and Molecular Medicine, Amrita Vishwa Vidapeetham, Kochi, Kerala, India
| | - Kohei Ohta
- Laboratory of Marine Biology, Faculty of Agriculture, Kyushu University, Fukouka, Japan
| | - Masaru Nakamura
- Sesoko Station, Tropical Biosphere Research Center, University of the Ryukyus, Okinawa, Japan.,Research Center, Okinawa Churashima Foundation, Okinawa, Japan
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30
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The Genetic and Endoplasmic Reticulum-Mediated Molecular Mechanisms of Primary Open-Angle Glaucoma. Int J Mol Sci 2020; 21:ijms21114171. [PMID: 32545285 PMCID: PMC7312987 DOI: 10.3390/ijms21114171] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 06/04/2020] [Accepted: 06/09/2020] [Indexed: 12/14/2022] Open
Abstract
Glaucoma is a heterogenous, chronic, progressive group of eye diseases, which results in irreversible loss of vision. There are several types of glaucoma, whereas the primary open-angle glaucoma (POAG) constitutes the most common type of glaucoma, accounting for three-quarters of all glaucoma cases. The pathological mechanisms leading to POAG pathogenesis are multifactorial and still poorly understood, but it is commonly known that significantly elevated intraocular pressure (IOP) plays a crucial role in POAG pathogenesis. Besides, genetic predisposition and aggregation of abrogated proteins within the endoplasmic reticulum (ER) lumen and subsequent activation of the protein kinase RNA-like endoplasmic reticulum kinase (PERK)-dependent unfolded protein response (UPR) signaling pathway may also constitute important factors for POAG pathogenesis at the molecular level. Glaucoma is commonly known as a ‘silent thief of sight’, as it remains asymptomatic until later stages, and thus its diagnosis is frequently delayed. Thereby, detailed knowledge about the glaucoma pathophysiology is necessary to develop both biochemical and genetic tests to improve its early diagnosis as well as develop a novel, ground-breaking treatment strategy, as currently used medical therapies against glaucoma are limited and may evoke numerous adverse side-effects in patients.
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31
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Wang H, Xue W, Ouyang W, Jiang X, Jiang X. miR-23a-3p/SIX1 regulates glucose uptake and proliferation through GLUT3 in head and neck squamous cell carcinomas. J Cancer 2020; 11:2529-2539. [PMID: 32201523 PMCID: PMC7066005 DOI: 10.7150/jca.30995] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2018] [Accepted: 01/15/2020] [Indexed: 02/06/2023] Open
Abstract
SIX1 overexpression has been reported in several cancers. However, its involvement in head and neck squamous cell carcinoma (HNSCC) remains unclear. In this study we investigated the clinical significance and biological roles of SIX1 in HNSCC. SIX1 expression was upregulated in HNSCC and correlated with TNM stage and nodal metastasis. Analysis of TCGA dataset demonstrated that high SIX1 expression correlated with poor patient prognosis. Overexpression of SIX1 in the Fadu cell line upregulated cell proliferation, colony formation, glucose uptake and ATP production. In contrast, SIX1 depletion in the Detroit562 cell line downregulated cell proliferation, colony formation, glucose uptake and ATP production. We analyzed a series of genes involved in glucose metabolism and found that SIX1 overexpression upregulated GLUT3, an important glucose transporter, at both mRNA and protein levels. Using the TRANSFAC database, we found that SIX1 had potential binding sites on the GLUT3 promoter, which was validated by chromatin immunoprecipitation (ChIP) assays. Next, we focused on miR-23a-3p, which could target SIX1 in HNSCC cells. The miR-23a-3p mimic downregulated SIX1 expression while the miR-23a-3p inhibitor upregulated SIX1 expression. The binding of miR-23a-3p to the 3'-UTR of SIX1 was confirmed using the luciferase reporter assay. Analysis of TCGA dataset showed a negative correlation between the miR-23a-3p and SIX1. Furthermore, the miR-23a-3p mimic inhibited cell proliferation, ATP production and glucose uptake, which could be rescued by transfection with the SIX1 plasmid. In summary, our study demonstrated that SIX1 facilitated HNSCC cell growth through regulation of GLUT3 and glucose uptake. miR-23a-3p targeted the SIX1/GLUT3 axis and suppressed glucose uptake and proliferation in HNSCC.
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Affiliation(s)
- Hongming Wang
- Department of Otolaryngology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Weishuang Xue
- Department of Neurology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Wunyu Ouyang
- Department of Otolaryngology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Xiaoze Jiang
- Department of Otolaryngology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Xuejun Jiang
- Department of Otolaryngology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
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32
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Xu C, Dai Y, Mohsin A, Hang H, Zhuang Y, Guo M. Mapping molecular pathways for embryonic Sertoli cells derivation based on differentiation model of mouse embryonic stem cells. Stem Cell Res Ther 2020; 11:85. [PMID: 32102677 PMCID: PMC7045406 DOI: 10.1186/s13287-020-01600-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Revised: 02/07/2020] [Accepted: 02/11/2020] [Indexed: 12/27/2022] Open
Abstract
Background Embryonic Sertoli cells (eSCs) have been known for playing important roles in male reproductive development system. In current studies, eSCs were mainly generated from induced intermediate mesoderm. The deriving mechanism of eSCs has been unclear so far. Therefore, this work was aimed to reveal the molecular pathways during derivation of eSCs. Methods In this scenario, a differentiation model from mouse embryonic stem cells (mESCs) to eSCs was established through spatiotemporal control of 5 key factors, Wilms tumor 1 homolog (Wt1), GATA binding protein 4 (Gata4), nuclear receptor subfamily 5, group A, member 1 (Nr5a1, i.e., Sf1), SRY (sex determining region Y)-box 9 (Sox9), doublesex, and mab-3 related transcription factor 1 (Dmrt1). To investigate the molecular mechanism, these key factors were respectively manipulated through a light-switchable (light-on) system, tetracycline-switchable (Tet-on) system, and CRISPR/Cas9 knock out (KO) system. Results Via the established approach, some embryonic Sertoli-like cells (eSLCs) were induced from mESCs and formed ring-like or tubular-like structures. The key factors were respectively manipulated and revealed their roles in the derivation of these eSLCs. Based on these results, some molecular pathways were mapped during the development of coelomic epithelial somatic cells to eSCs. Conclusions This differentiation model provided a high controllability of some key factors and brought a novel insight into the deriving mechanism of Sertoli cells. Supplementary information accompanies this paper at 10.1186/s13287-020-01600-2.
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Affiliation(s)
- Chenze Xu
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, 200237, People's Republic of China
| | - Yichen Dai
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, 200237, People's Republic of China
| | - Ali Mohsin
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, 200237, People's Republic of China
| | - Haifeng Hang
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, 200237, People's Republic of China.,Engineering Research Centre of Processes System, Ministry of Education, East China University of Science and Technology, 130 Meilong Rd., Shanghai, 200237, China
| | - Yingping Zhuang
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, 200237, People's Republic of China.,Engineering Research Centre of Processes System, Ministry of Education, East China University of Science and Technology, 130 Meilong Rd., Shanghai, 200237, China
| | - Meijin Guo
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, 200237, People's Republic of China. .,Engineering Research Centre of Processes System, Ministry of Education, East China University of Science and Technology, 130 Meilong Rd., Shanghai, 200237, China. .,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.
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33
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Creed TM, Baldeosingh R, Eberly CL, Schlee CS, Kim M, Cutler JA, Pandey A, Civin CI, Fossett NG, Kingsbury TJ. The PAX-SIX-EYA-DACH network modulates GATA-FOG function in fly hematopoiesis and human erythropoiesis. Development 2020; 147:dev.177022. [PMID: 31806659 DOI: 10.1242/dev.177022] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Accepted: 11/25/2019] [Indexed: 12/15/2022]
Abstract
The GATA and PAX-SIX-EYA-DACH transcriptional networks (PSEDNs) are essential for proper development across taxa. Here, we demonstrate novel PSEDN roles in vivo in Drosophila hematopoiesis and in human erythropoiesis in vitro Using Drosophila genetics, we show that PSEDN members function with GATA to block lamellocyte differentiation and maintain the prohemocyte pool. Overexpression of human SIX1 stimulated erythroid differentiation of human erythroleukemia TF1 cells and primary hematopoietic stem-progenitor cells. Conversely, SIX1 knockout impaired erythropoiesis in both cell types. SIX1 stimulation of erythropoiesis required GATA1, as SIX1 overexpression failed to drive erythroid phenotypes and gene expression patterns in GATA1 knockout cells. SIX1 can associate with GATA1 and stimulate GATA1-mediated gene transcription, suggesting that SIX1-GATA1 physical interactions contribute to the observed functional interactions. In addition, both fly and human SIX proteins regulated GATA protein levels. Collectively, our findings demonstrate that SIX proteins enhance GATA function at multiple levels, and reveal evolutionarily conserved cooperation between the GATA and PSEDN networks that may regulate developmental processes beyond hematopoiesis.
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Affiliation(s)
- T Michael Creed
- Center for Stem Cell Biology & Regenerative Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Rajkumar Baldeosingh
- Center for Vascular and Inflammatory Diseases University of Maryland School of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA.,Department of Pathology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.,Manipal Academy of Higher Education (MAHE), Manipal 576104, Karnataka, India
| | - Christian L Eberly
- Center for Stem Cell Biology & Regenerative Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Caroline S Schlee
- Center for Stem Cell Biology & Regenerative Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - MinJung Kim
- Center for Stem Cell Biology & Regenerative Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA.,Department of Pediatrics, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Jevon A Cutler
- McKusick-Nathans Institute of Genetic Medicine, Departments of Biological Chemistry, Oncology and Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Akhilesh Pandey
- McKusick-Nathans Institute of Genetic Medicine, Departments of Biological Chemistry, Oncology and Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Curt I Civin
- Center for Stem Cell Biology & Regenerative Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA.,Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA.,Department of Physiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.,Department of Pediatrics, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Nancy G Fossett
- Center for Stem Cell Biology & Regenerative Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA .,Center for Vascular and Inflammatory Diseases University of Maryland School of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA.,Department of Pathology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Tami J Kingsbury
- Center for Stem Cell Biology & Regenerative Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA .,Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA.,Department of Physiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
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Mäkelä JA, Koskenniemi JJ, Virtanen HE, Toppari J. Testis Development. Endocr Rev 2019; 40:857-905. [PMID: 30590466 DOI: 10.1210/er.2018-00140] [Citation(s) in RCA: 189] [Impact Index Per Article: 31.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2018] [Accepted: 07/17/2018] [Indexed: 12/28/2022]
Abstract
Production of sperm and androgens is the main function of the testis. This depends on normal development of both testicular somatic cells and germ cells. A genetic program initiated from the Y chromosome gene sex-determining region Y (SRY) directs somatic cell specification to Sertoli cells that orchestrate further development. They first guide fetal germ cell differentiation toward spermatogenic destiny and then take care of the full service to spermatogenic cells during spermatogenesis. The number of Sertoli cells sets the limits of sperm production. Leydig cells secrete androgens that determine masculine development. Testis development does not depend on germ cells; that is, testicular somatic cells also develop in the absence of germ cells, and the testis can produce testosterone normally to induce full masculinization in these men. In contrast, spermatogenic cell development is totally dependent on somatic cells. We herein review germ cell differentiation from primordial germ cells to spermatogonia and development of the supporting somatic cells. Testicular descent to scrota is necessary for normal spermatogenesis, and cryptorchidism is the most common male birth defect. This is a mild form of a disorder of sex differentiation. Multiple genetic reasons for more severe forms of disorders of sex differentiation have been revealed during the last decades, and these are described along with the description of molecular regulation of testis development.
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Affiliation(s)
- Juho-Antti Mäkelä
- Research Centre for Integrative Physiology and Pharmacology, Institute of Biomedicine, University of Turku, Turku, Finland
| | - Jaakko J Koskenniemi
- Research Centre for Integrative Physiology and Pharmacology, Institute of Biomedicine, University of Turku, Turku, Finland.,Department of Pediatrics, Turku University Hospital, Turku, Finland
| | - Helena E Virtanen
- Research Centre for Integrative Physiology and Pharmacology, Institute of Biomedicine, University of Turku, Turku, Finland
| | - Jorma Toppari
- Research Centre for Integrative Physiology and Pharmacology, Institute of Biomedicine, University of Turku, Turku, Finland.,Department of Pediatrics, Turku University Hospital, Turku, Finland
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35
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Lin J, He J, Liang A, Wang F. Transcriptome profiling and dimorphic expression of sex-related genes in fifth-instar nymphs of Sogatella furcifera, an important rice pest. Genomics 2019; 112:1105-1111. [PMID: 31247330 DOI: 10.1016/j.ygeno.2019.06.024] [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: 05/12/2019] [Revised: 06/08/2019] [Accepted: 06/21/2019] [Indexed: 01/04/2023]
Abstract
Sogatella furcifera is an important rice pest. In order to understand the molecular basis of the sex determination in this pest, we performed de novo transcriptome sequencing of six cDNA libraries (three biological replicates) of female and male fifth-instar nymphs. Total 65,199 unigenes were obtained, with an average length of 971.5 bp and N50 length of 1708 bp. 20,287 open reading frames (ORFs) were predicted and annotated. Total 1019 differentially expressed genes with 873 upregulated and 146 downregulated were found in male compared to female. Total 164 sex-determining genes were identified, including the key sex-determining genes in fruit flies, such as Sxl, tra, dsx, etc. It implied that the sex determination mechanisms of S. furcifera may be the same as that of fruit flies. This study provided transcriptome resource as a fundamental support for future functional studies to elucidate the sex determination regulatory networks governing sexual dimorphism of S. furcifera.
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Affiliation(s)
- Jia Lin
- State Key Laboratory for Biocontrol and Institute of Entomology, Sun Yat-sen University, Guangzhou 510275, China.
| | - Jingyi He
- State Key Laboratory for Biocontrol and Institute of Entomology, Sun Yat-sen University, Guangzhou 510275, China
| | - Anwen Liang
- State Key Laboratory for Biocontrol and Institute of Entomology, Sun Yat-sen University, Guangzhou 510275, China
| | - Fanghai Wang
- State Key Laboratory for Biocontrol and Institute of Entomology, Sun Yat-sen University, Guangzhou 510275, China.
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36
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Stévant I, Nef S. Genetic Control of Gonadal Sex Determination and Development. Trends Genet 2019; 35:346-358. [PMID: 30902461 DOI: 10.1016/j.tig.2019.02.004] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2018] [Revised: 02/15/2019] [Accepted: 02/23/2019] [Indexed: 10/27/2022]
Abstract
Sex determination is the process by which the bipotential gonads develop as either testes or ovaries. With two distinct potential outcomes, the gonadal primordium offers a unique model for the study of cell fate specification and how distinct cell populations diverge from multipotent progenitors. This review focuses on recent advances in our understanding of the genetic programs and epigenetic mechanisms that regulate gonadal sex determination and the regulation of cell fate commitment in the bipotential gonads. We rely primarily on mouse data to illuminate the complex and dynamic genetic programs controlling cell fate decision and sex-specific cell differentiation during gonadal formation and gonadal sex determination.
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Affiliation(s)
- Isabelle Stévant
- Department of Genetic Medicine and Development, University of Geneva, 1211 Geneva, Switzerland; iGE3, Institute of Genetics and Genomics of Geneva, University of Geneva, 1211 Geneva, Switzerland; SIB, Swiss Institute of Bioinformatics, University of Geneva, 1211 Geneva, Switzerland
| | - Serge Nef
- Department of Genetic Medicine and Development, University of Geneva, 1211 Geneva, Switzerland; iGE3, Institute of Genetics and Genomics of Geneva, University of Geneva, 1211 Geneva, Switzerland.
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Xu C, Mohsin A, Luo Y, Xie L, Peng Y, Wang Q, Hang H, Zhuang Y, Guo M. Differentiation roadmap of embryonic Sertoli cells derived from mouse embryonic stem cells. Stem Cell Res Ther 2019; 10:81. [PMID: 30850007 PMCID: PMC6408820 DOI: 10.1186/s13287-019-1180-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Revised: 02/14/2019] [Accepted: 02/18/2019] [Indexed: 12/13/2022] Open
Abstract
Background Embryonic Sertoli cells (eSCs) play an important role in sex determination and in male gonad development which makes them a very useful cell type for therapeutic applications. However, the deriving mechanism of Sertoli cells has been unclear and challenging to create a large number of quality eSCs. Therefore, this study aimed to create the eSCs induced from mouse embryonic stem (mES) cells by regulating defined factors and to explore the relevant regulatory mechanism. Methods Six inducing factors, Sry, Sox9, SF1, WT1, GATA4, and Dmrt1, were respectively transduced into mES cells by lentiviral infection according to the experimental design. The test groups were identified by development stage-specific markers, AMH, Emx2, SF1, and FasL, using flow cytometry. Induced eSCs were determined by FasL and AMH biomarkers under immunofluorescence, immunocytochemistry, and flow cytometry. Moreover, the pluripotency markers, gonad development-related markers, epithelial markers and mesenchymal markers in test groups were transcriptionally determined by qPCR. Results In this study, the co-overexpression of all the six factors effectively produced a large population of eSCs from mES cells in 35 days of culturing. These eSCs were capable of forming tubular-like and ring-like structures with functional performance. The results of flow cytometry indicated that the upregulation of GATA4 and WT1 contributed to the growth of somatic cells in the coelomic epithelium regarded as the main progenitor cells of eSCs. Whereas, SF1 facilitated the development of eSC precursor cells, and Sry and Sox9 promoted the determination of male development. Moreover, the overexpression of Dmrt1 was essential for the maintenance of eSCs and some of their specific surface biomarkers such as FasL. The cellular morphology, biomarker identification, and transcriptomic analysis aided in exploring the regulatory mechanism of deriving eSCs from mES cells. Conclusion Conclusively, we have elucidated a differentiation roadmap of eSCs derived from mES cells with a relevant regulatory mechanism. Through co-overexpression of all these six factors, a large population of eSCs was successfully induced occupying 24% of the whole cell population (1 × 105 cells/cm2). By adopting this approach, a mass of embryonic Sertoli cells can be generated for the purpose of co-culture technique, organ transplantation, gonadal developmental and sex determination researches. Electronic supplementary material The online version of this article (10.1186/s13287-019-1180-6) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Chenze Xu
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, 130 Meilong Rd., Shanghai, 200237, People's Republic of China
| | - Ali Mohsin
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, 130 Meilong Rd., Shanghai, 200237, People's Republic of China
| | - Yanxia Luo
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, 130 Meilong Rd., Shanghai, 200237, People's Republic of China
| | - Lili Xie
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, 130 Meilong Rd., Shanghai, 200237, People's Republic of China
| | - Yan Peng
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, 130 Meilong Rd., Shanghai, 200237, People's Republic of China
| | - Qizheng Wang
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, 130 Meilong Rd., Shanghai, 200237, People's Republic of China
| | - Haifeng Hang
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, 130 Meilong Rd., Shanghai, 200237, People's Republic of China.,Engineering Research Centre of Processes System, Ministry of Education, East China University of Science and Technology, 130 Meilong Rd., Shanghai, 200237, People's Republic of China
| | - Yingping Zhuang
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, 130 Meilong Rd., Shanghai, 200237, People's Republic of China.,Engineering Research Centre of Processes System, Ministry of Education, East China University of Science and Technology, 130 Meilong Rd., Shanghai, 200237, People's Republic of China
| | - Meijin Guo
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, 130 Meilong Rd., Shanghai, 200237, People's Republic of China. .,Engineering Research Centre of Processes System, Ministry of Education, East China University of Science and Technology, 130 Meilong Rd., Shanghai, 200237, People's Republic of China.
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38
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Sullivan CH, Majumdar HD, Neilson KM, Moody SA. Six1 and Irx1 have reciprocal interactions during cranial placode and otic vesicle formation. Dev Biol 2019; 446:68-79. [PMID: 30529252 PMCID: PMC6349505 DOI: 10.1016/j.ydbio.2018.12.003] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2018] [Revised: 12/02/2018] [Accepted: 12/03/2018] [Indexed: 01/04/2023]
Abstract
The specialized sensory organs of the vertebrate head are derived from thickened patches of cells in the ectoderm called cranial sensory placodes. The developmental program that generates these placodes and the genes that are expressed during the process have been studied extensively in a number of animals, yet very little is known about how these genes regulate one another. We previously found via a microarray screen that Six1, a known transcriptional regulator of cranial placode fate, up-regulates Irx1 in ectodermal explants. In this study, we investigated the transcriptional relationship between Six1 and Irx1 and found that they reciprocally regulate each other throughout cranial placode and otic vesicle formation. Although Irx1 expression precedes that of Six1 in the neural border zone, its continued and appropriately patterned expression in the pre-placodal region (PPR) and otic vesicle requires Six1. At early PPR stages, Six1 expands the Irx1 domain, but this activity subsides over time and changes to a predominantly repressive effect. Likewise, Irx1 initially expands Six1 expression in the PPR, but later represses it. We also found that Irx1 and Sox11, a known direct target of Six1, reciprocally affect each other. This work demonstrates that the interactions between Six1 and Irx1 are continuous during PPR and placode development and their transcriptional effects on one another change over developmental time.
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Affiliation(s)
- Charles H Sullivan
- Department of Biology, Grinnell College, Grinnell, IA, 50112, USA; bDepartment of Anatomy and Cell Biology, George Washington University School of Medicine and Health Sciences, 2300 I (eye) Street, N.W., Washington DC 20037, USA
| | - Himani D Majumdar
- bDepartment of Anatomy and Cell Biology, George Washington University School of Medicine and Health Sciences, 2300 I (eye) Street, N.W., Washington DC 20037, USA
| | - Karen M Neilson
- bDepartment of Anatomy and Cell Biology, George Washington University School of Medicine and Health Sciences, 2300 I (eye) Street, N.W., Washington DC 20037, USA
| | - Sally A Moody
- bDepartment of Anatomy and Cell Biology, George Washington University School of Medicine and Health Sciences, 2300 I (eye) Street, N.W., Washington DC 20037, USA.
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39
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Larose H, Shami AN, Abbott H, Manske G, Lei L, Hammoud SS. Gametogenesis: A journey from inception to conception. Curr Top Dev Biol 2019; 132:257-310. [PMID: 30797511 PMCID: PMC7133493 DOI: 10.1016/bs.ctdb.2018.12.006] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Gametogenesis, the process of forming mature germ cells, is an integral part of both an individual's and a species' health and well-being. This chapter focuses on critical male and female genetic and epigenetic processes underlying normal gamete formation through their differentiation to fertilization. Finally, we explore how knowledge gained from this field has contributed to progress in areas with great clinical promise, such as in vitro gametogenesis.
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Affiliation(s)
- Hailey Larose
- Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI, United States
| | | | - Haley Abbott
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Gabriel Manske
- Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Lei Lei
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, United States; Department of Biomedical Engineering, University of Michigan Medical School, Ann Arbor, MI, United States.
| | - Saher Sue Hammoud
- Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI, United States; Department of Obstetrics and Gynecology, University of Michigan Medical School, Ann Arbor, MI, United States; Department of Urology, University of Michigan Medical School, Ann Arbor, MI, United States.
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40
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Nef S, Stévant I, Greenfield A. Characterizing the bipotential mammalian gonad. Curr Top Dev Biol 2019; 134:167-194. [DOI: 10.1016/bs.ctdb.2019.01.002] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
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41
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Gregoire EP, Stevant I, Chassot AA, Martin L, Lachambre S, Mondin M, de Rooij DG, Nef S, Chaboissier MC. NRG1 signalling regulates the establishment of Sertoli cell stock in the mouse testis. Mol Cell Endocrinol 2018; 478:17-31. [PMID: 30040984 DOI: 10.1016/j.mce.2018.07.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2017] [Revised: 05/31/2018] [Accepted: 07/08/2018] [Indexed: 10/28/2022]
Abstract
Testis differentiation requires high levels of proliferation of progenitor cells that give rise to two cell lineages forming the testis, the Sertoli and the Leydig cells. Hence defective cell cycling leads to testicular dysgenesis that has profound effects on androgen production and fertility. The growth factor NRG1 has been implicated in adult Leydig cell proliferation, but a potential function in the fetal testis has not been analysed to date. Here we show that Nrg1 and its receptors ErbB2/3 are already expressed in early gonadal development. Using tissue-specific deletion, we further demonstrate that Nrg1 is required in a dose-dependent manner to induce proliferation of Sertoli progenitor cells and then differentiated Sertoli cells. As a result of reduced numbers of Sertoli cells, Nrg1 knockout mice display a delay in testis differentiation and defects in sex cord partitioning. Taken together Nrg1 signalling is essential for the establishment of the stock of Sertoli cells and thus required to prevent testicular hypoplasia.
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Affiliation(s)
| | - Isabelle Stevant
- Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, Switzerland
| | | | - Luc Martin
- Université Côte d'Azur, CNRS, Inserm, iBV, France
| | | | | | - Dirk G de Rooij
- Reproductive Biology Group, Division of Developmental Biology, Department of Biology, Faculty of Science, Utrecht University, Utrecht 3584 CH, the Netherlands
| | - Serge Nef
- Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, Switzerland
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Nagaraja MR, Gubbala SP, Delphine Silvia CRW, Amanchy R. Molecular diagnostics of disorders of sexual development: an Indian survey and systems biology perspective. Syst Biol Reprod Med 2018; 65:105-120. [PMID: 30550360 DOI: 10.1080/19396368.2018.1549619] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
We aimed to survey the monogenic causes of disorders of sex development (DSD) and thereby its prevalence in India. This study revealed mutations resulting in androgen insensitivity syndrome, 5α-reductase type 2 deficiency, and gonadal dysgenesis were commonly reported. Intriguingly, AR deficits were the most prevalent (32 mutations) and of 11/26 missense mutations were in exons 4-8 (encoding ligand binding domain). The unique features of SRD5A2 defects were p.R246Q (most prevalent) and p.G196S could be mutational hotspots, dual gene defects (p.A596T in AR and p.G196S in SRD5A2) in a patient with hypospadias and novel 8 nucleotide deletion (exon 1) found in a patient with perineal hypospadias. Deficits in SRY, WT1, DHH, NR5A1, and DMRT1 caused 46,XY gonadal dysgenesis. Notably, mutations in AR, SRD5A2, MAMLD1, WT1, and MAP3K1 have led to hypospadias and only one CYP19A1 mutation caused aromatase deficiency was reported to date. Data mining from various databases has not only reinforced the role of well-established genes (e.g., SRY, WT1, DHH, NR5A1, DMRT1, AR, SRD5A2, MAMLD1) involved in DSD but also provided us 12 more potential candidate genes (ACVR1, AMHR2, CTNNB1, CYP11A1, CYP19A1, FGFR2, FGF9, PRKACA, PRKACG, SMAD9, TERT, ZFPM2), which benefit from a close association with the well-established genes involved in DSD and might be useful to screen owing to their direct gene-phenotype relationship or through direct functional interaction. As more genes have been revealed in relation to DSD, we believe ultimately it holds a better scenario for therapeutic regimen. Despite the advances in translational medicine, hospitals are yet to adopt genetic testing and counseling facilities in India that shall have potential impact on clinical diagnosis. Abbreviations: 5α-RD2: 5α-Reductase type 2; AIS: androgen insensitivity syndrome; AMH: antimullerian hormone; AMHR: antimullerian hormone receptor; AR: androgen receptor gene; CAH: congenital adrenal hyperplasia; CAIS: complete AIS; CAH: congenital adrenal hyperplasia; CHH: congenital hypogonadotropic hypogonadism; CXORF6: chromosome X open reading frame 6 gene; CYP19A1: cytochrome P450 family 19 subfamily A member 1 gene; DHT: dihydrotestosterone; DMRT1: double sex and mab-3 related transcription factor 1 gene; DSD: disorders of sexual development; GD: gonadal dysgenesis; HGMD: human gene mutation database; IH: isolated hypospadias; MAMLD1: mastermind like domain containing 1 gene; MIS: mullerian inhibiting substance; NTD: N-terminal domain; OT DSD: ovotesticular DSD; PAIS: partial AIS; SOX9: SRY-related HMG-box 9 gene; SRY: sex-determining region Y gene; STAR: steroidogenic acute regulatory protein gene; SRD5A2: steroid 5 alpha-reductase 2 gene; T DSD: testicular DSD; T: testosterone; WNT4: Wnt family member 4 gene; WT1: Wilms tumor 1 gene; Δ4: androstenedione.
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Affiliation(s)
- M R Nagaraja
- a Department of Biochemistry , Akash Institute of Medical Sciences & Research Centre , Bangalore , India
| | - Satya Prakash Gubbala
- b Division of Pharmacology and Toxicology , CSIR- Indian Institute of Chemical Technology , Hyderabad , India
| | - C R Wilma Delphine Silvia
- a Department of Biochemistry , Akash Institute of Medical Sciences & Research Centre , Bangalore , India
| | - Ramars Amanchy
- b Division of Pharmacology and Toxicology , CSIR- Indian Institute of Chemical Technology , Hyderabad , India
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Takahashi M, Tamura M, Sato S, Kawakami K. Mice doubly deficient in Six4 and Six5 show ventral body wall defects reproducing human omphalocele. Dis Model Mech 2018; 11:dmm.034611. [PMID: 30237319 PMCID: PMC6215434 DOI: 10.1242/dmm.034611] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Accepted: 09/05/2018] [Indexed: 01/11/2023] Open
Abstract
Omphalocele is a human congenital anomaly in ventral body wall closure and may be caused by impaired formation of the primary abdominal wall (PAW) and/or defects in abdominal muscle development. Here, we report that mice doubly deficient in homeobox genes Six4 and Six5 showed the same ventral body wall closure defects as those seen in human omphalocele. SIX4 and SIX5 were localized in surface ectodermal cells and somatic mesoderm-derived mesenchymal and coelomic epithelial cells (CECs) in the PAW. Six4-/-;Six5-/- fetuses exhibited a large omphalocele with protrusion of both the liver and intestine, or a small omphalocele with protrusion of the intestine, with complete penetrance. The umbilical ring of Six4-/-;Six5-/- embryos was shifted anteriorly and its lateral size was larger than that of normal embryos at the E11.5 stage, before the onset of myoblast migration into the PAW. The proliferation rates of surface ectodermal cells in the left and right PAW and somatic mesoderm-derived cells in the right PAW were lower in Six4-/-;Six5-/- embryos than those of wild-type embryos at E10.5. The transition from CECs of the PAW to rounded mesothelial progenitor cells was impaired and the inner coelomic surface of the PAW was relatively smooth in Six4-/-;Six5-/- embryos at E11.25. Furthermore, Six4 overexpression in CECs of the PAW promoted ingression of CECs. Taken together, our results suggest that Six4 and Six5 are required for growth and morphological change of the PAW, and the impairment of these processes is linked to the abnormal positioning and expansion of the umbilical ring, which results in omphalocele.
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Affiliation(s)
- Masanori Takahashi
- Division of Biology, Center for Molecular Medicine, Jichi Medical University, 3311-1, Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan
| | - Masaru Tamura
- Technology and Development Team for Mouse Phenotype Analysis, RIKEN BioResource Center, 3-1-1, Koyadai, Tsukuba, Ibaraki, 305-0074, Japan
| | - Shigeru Sato
- Division of Biology, Center for Molecular Medicine, Jichi Medical University, 3311-1, Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan
| | - Kiyoshi Kawakami
- Division of Biology, Center for Molecular Medicine, Jichi Medical University, 3311-1, Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan
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Mesothelial to mesenchyme transition as a major developmental and pathological player in trunk organs and their cavities. Commun Biol 2018; 1:170. [PMID: 30345394 PMCID: PMC6191446 DOI: 10.1038/s42003-018-0180-x] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2018] [Accepted: 09/28/2018] [Indexed: 12/18/2022] Open
Abstract
The internal organs embedded in the cavities are lined by an epithelial monolayer termed the mesothelium. The mesothelium is increasingly implicated in driving various internal organ pathologies, as many of the normal embryonic developmental pathways acting in mesothelial cells, such as those regulating epithelial-to-mesenchymal transition, also drive disease progression in adult life. Here, we summarize observations from different animal models and organ systems that collectively point toward a central role of epithelial-to-mesenchymal transition in driving tissue fibrosis, acute scarring, and cancer metastasis. Thus, drugs targeting pathways of mesothelium’s transition may have broad therapeutic benefits in patients suffering from these diseases. Tim Koopmans and Yuval Rinkevich review recent findings linking the mesothelium’s embryonic programs that drive epithelial-to-mesenchyme transition with adult pathologies, such as fibrosis, acute scarring, and cancer metastasis. They highlight new avenues for drug development that would target pathways of the mesothelium’s mesenchymal transition.
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45
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Rotgers E, Jørgensen A, Yao HHC. At the Crossroads of Fate-Somatic Cell Lineage Specification in the Fetal Gonad. Endocr Rev 2018; 39:739-759. [PMID: 29771299 PMCID: PMC6173476 DOI: 10.1210/er.2018-00010] [Citation(s) in RCA: 97] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2018] [Accepted: 05/09/2018] [Indexed: 01/07/2023]
Abstract
The reproductive endocrine systems are vastly different between males and females. This sexual dimorphism of the endocrine milieu originates from sex-specific differentiation of the somatic cells in the gonads during fetal life. Most gonadal somatic cells arise from the adrenogonadal primordium. After separation of the adrenal and gonadal primordia, the gonadal somatic cells initiate sex-specific differentiation during gonadal sex determination with the specification of the supporting cell lineages: Sertoli cells in the testis vs granulosa cells in the ovary. The supporting cell lineages then facilitate the differentiation of the steroidogenic cell lineages, Leydig cells in the testis and theca cells in the ovary. Proper differentiation of these cell types defines the somatic cell environment that is essential for germ cell development, hormone production, and establishment of the reproductive tracts. Impairment of lineage specification and function of gonadal somatic cells can lead to disorders of sexual development (DSDs) in humans. Human DSDs and processes for gonadal development have been successfully modeled using genetically modified mouse models. In this review, we focus on the fate decision processes from the initial stage of formation of the adrenogonadal primordium in the embryo to the maintenance of the somatic cell identities in the gonads when they become fully differentiated in adulthood.
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Affiliation(s)
- Emmi Rotgers
- Reproductive Developmental Biology Group, National Institute of Environmental Health Sciences, Durham, North Carolina
| | - Anne Jørgensen
- Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.,International Research and Research Training Center in Endocrine Disruption of Male Reproduction and Child Health, Copenhagen, Denmark
| | - Humphrey Hung-Chang Yao
- Reproductive Developmental Biology Group, National Institute of Environmental Health Sciences, Durham, North Carolina
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Yang Y, Workman S, Wilson M. The molecular pathways underlying early gonadal development. J Mol Endocrinol 2018; 62:JME-17-0314. [PMID: 30042122 DOI: 10.1530/jme-17-0314] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Revised: 07/18/2018] [Accepted: 07/24/2018] [Indexed: 12/30/2022]
Abstract
The body of knowledge surrounding reproductive development spans the fields of genetics, anatomy, physiology and biomedicine, to build a comprehensive understanding of the later stages of reproductive development in humans and animal models. Despite this, there remains much to learn about the bi-potential progenitor structure that the ovary and testis arise from, known as the genital ridge (GR). This tissue forms relatively late in embryonic development and has the potential to form either the ovary or testis, which in turn produce hormones required for development of the rest of the reproductive tract. It is imperative that we understand the genetic networks underpinning GR development if we are to begin to understand abnormalities in the adult. This is particularly relevant in the contexts of disorders of sex development (DSDs) and infertility, two conditions that many individuals struggle with worldwide, with often no answers as to their aetiology. Here, we review what is known about the genetics of GR development. Investigating the genetic networks required for GR formation will not only contribute to our understanding of the genetic regulation of reproductive development, it may in turn open new avenues of investigation into reproductive abnormalities and later fertility issues in the adult.
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Affiliation(s)
- Yisheng Yang
- Y Yang, Anatomy, University of Otago, Dunedin, New Zealand
| | | | - Megan Wilson
- M Wilson , Anatomy, University of Otago, Dunedin, New Zealand
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Yao R, Yu D, Wang J, Wang X, Shen Y. A rare unbalanced Y:autosome translocation in a Turner syndrome patient. J Pediatr Endocrinol Metab 2018; 31:349-353. [PMID: 29306927 DOI: 10.1515/jpem-2017-0244] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2017] [Accepted: 11/28/2017] [Indexed: 11/15/2022]
Abstract
BACKGROUND Y:autosome translocations are reported to be associated with male infertility and azoospermia. Female cases with Y:autosome translocation are extremely rare. CASE PRESENTATION We report a unique case of a rare unbalanced translocation t(Y;13) in a 12-year-old girl with Turner syndrome. Combined cytogenetic testing helped to demonstrate the detail of rare chromosomal structural rearrangement in this patient. CONCLUSIONS The presented case showed femaleness phenotype and failure of masculinization with presence of Y chromosome and the SRY gene. She was treated with growth hormone (GH) therapy after confirming the presence of only female internal gonad with laparoscopy.
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Affiliation(s)
- Ruen Yao
- Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, P.R. China
| | - Ding Yu
- Department of Endocrinology and Metabolism, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, P.R. China
| | - Jian Wang
- Department of Endocrinology and Metabolism, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, P.R. China
| | - Xiumin Wang
- Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, P.R. China
| | - Yiping Shen
- Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, P.R. China.,Boston Children's Hospital, Boston, MA 02115, USA, Phone: +617-355-6000
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Fernández-Pérez D, Brieño-Enríquez MA, Isoler-Alcaraz J, Larriba E, Del Mazo J. MicroRNA dynamics at the onset of primordial germ and somatic cell sex differentiation during mouse embryonic gonad development. RNA (NEW YORK, N.Y.) 2018; 24:287-303. [PMID: 29187591 PMCID: PMC5824349 DOI: 10.1261/rna.062869.117] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/05/2017] [Accepted: 11/27/2017] [Indexed: 06/07/2023]
Abstract
In mammals, commitment and specification of germ cell lines involves complex programs that include sex differentiation, control of proliferation, and meiotic initiation. Regulation of these processes is genetically controlled by fine-tuned mechanisms of gene regulation in which microRNAs (miRNAs) are involved. We have characterized, by small-RNA-seq and bioinformatics analyses, the miRNA expression patterns of male and female mouse primordial germ cells (PGCs) and gonadal somatic cells at embryonic stages E11.5, E12.5, and E13.5. Differential expression analyses revealed differences in the regulation of key miRNA clusters such as miR-199-214, miR-182-183-96, and miR-34c-5p, whose targets have defined roles during gonadal sexual determination in both germ and somatic cells. Extensive analyses of miRNA sequences revealed an increase in noncanonical isoforms on PGCs at E12.5 and dramatic changes of 3' isomiR expression and 3' nontemplate nucleotide additions in female PGCs at E13.5. Additionally, RT-qPCR analyses of genes encoding proteins involved in miRNA biogenesis and 3' nucleotide addition uncovered sexually and developmentally specific expression, characterized by the decay of Drosha, Dgcr8, and Xpo5 expression along gonadal development. These results demonstrate that miRNAs, their isomiRs, and miRNA machinery are differentially regulated and participate actively in gonadal sexual differentiation in both PGCs and gonadal somatic cells.
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Affiliation(s)
- Daniel Fernández-Pérez
- Department of Cellular and Molecular Biology, Centro de Investigaciones Biológicas (CSIC), Madrid 28040, Spain
| | - Miguel A Brieño-Enríquez
- Department of Cellular and Molecular Biology, Centro de Investigaciones Biológicas (CSIC), Madrid 28040, Spain
| | - Javier Isoler-Alcaraz
- Department of Cellular and Molecular Biology, Centro de Investigaciones Biológicas (CSIC), Madrid 28040, Spain
| | - Eduardo Larriba
- Department of Cellular and Molecular Biology, Centro de Investigaciones Biológicas (CSIC), Madrid 28040, Spain
| | - Jesús Del Mazo
- Department of Cellular and Molecular Biology, Centro de Investigaciones Biológicas (CSIC), Madrid 28040, Spain
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Carré GA, Siggers P, Xipolita M, Brindle P, Lutz B, Wells S, Greenfield A. Loss of p300 and CBP disrupts histone acetylation at the mouse Sry promoter and causes XY gonadal sex reversal. Hum Mol Genet 2018; 27:190-198. [PMID: 29145650 PMCID: PMC5886154 DOI: 10.1093/hmg/ddx398] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2017] [Revised: 10/31/2017] [Accepted: 11/01/2017] [Indexed: 01/08/2023] Open
Abstract
CREB-binding protein (CBP, CREBBP, KAT3A) and its closely related paralogue p300 (EP300, KAT3B), together termed p300/CBP, are histone/lysine acetyl-transferases that control gene expression by modifying chromatin-associated proteins. Here, we report roles for both of these chromatin-modifying enzymes in mouse sex determination, the process by which the embryonic gonad develops into a testis or an ovary. By targeting gene ablation to embryonic gonadal somatic cells using an inducible Cre line, we show that gonads lacking either gene exhibit major abnormalities of XY gonad development at 14.5 dpc, including partial sex reversal. Embryos lacking three out of four functional copies of p300/Cbp exhibit complete XY gonadal sex reversal and have greatly reduced expression of the key testis-determining genes Sry and Sox9. An analysis of histone acetylation at the Sry promoter in mutant gonads at 11.5 dpc shows a reduction in levels of the positive histone mark H3K27Ac. Our data suggest a role for CBP/p300 in testis determination mediated by control of histone acetylation at the Sry locus and reveal a novel element in the epigenetic control of Sry and mammalian sex determination. They also suggest possible novel causes of human disorders of sex development (DSD).
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Affiliation(s)
- Gwenn-Aël Carré
- Mammalian Genetics Unit, Medical Research Council, Harwell Institute, Oxfordshire OX11 0RD, UK
| | - Pam Siggers
- Mammalian Genetics Unit, Medical Research Council, Harwell Institute, Oxfordshire OX11 0RD, UK
| | - Marilena Xipolita
- Mammalian Genetics Unit, Medical Research Council, Harwell Institute, Oxfordshire OX11 0RD, UK
| | - Paul Brindle
- Department of Biochemistry, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
| | - Beat Lutz
- Institute of Physiological Chemistry, University Medical Center Mainz, 55128 Mainz, Germany
| | - Sara Wells
- Mary Lyon Centre, Medical Research Council, Harwell Institute, Oxfordshire OX11 0RD, UK
| | - Andy Greenfield
- Mammalian Genetics Unit, Medical Research Council, Harwell Institute, Oxfordshire OX11 0RD, UK
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von Kopylow K, Spiess AN. Human spermatogonial markers. Stem Cell Res 2017; 25:300-309. [PMID: 29239848 DOI: 10.1016/j.scr.2017.11.011] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2016] [Revised: 11/06/2017] [Accepted: 11/13/2017] [Indexed: 12/22/2022] Open
Abstract
In this review, we provide an up-to-date compilation of published human spermatogonial markers, with focus on the three nuclear subtypes Adark, Apale and B. In addition, we have extended our recently published list of putative spermatogonial markers with protein expression and RNA-sequencing data from the Human Protein Atlas and supported these by literature evidence. Most importantly, we have put substantial effort in acquiring a comprehensive list of new and potentially interesting markers by refiltering the raw data of 15 published germ cell expression datasets (four human, eleven rodent) and subsequent building of intersections to acquire a robust, cross-species set of spermatogonia-enriched or -specific transcripts.
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Affiliation(s)
- Kathrein von Kopylow
- Department of Andrology, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
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