دورية أكاديمية
COUP-TFII regulates early bipotential gonad signaling and commitment to ovarian progenitors.
العنوان: | COUP-TFII regulates early bipotential gonad signaling and commitment to ovarian progenitors. |
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المؤلفون: | Ferreira LGA; Laboratory of Molecular and Translational Endocrinology (LEMT), Endocrinology Division, Department of Medicine, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil.; Murdoch Children's Research Institute, Melbourne, Australia., Kizys MML; Laboratory of Molecular and Translational Endocrinology (LEMT), Endocrinology Division, Department of Medicine, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil., Gama GAC; Laboratory of Molecular and Translational Endocrinology (LEMT), Endocrinology Division, Department of Medicine, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil., Pachernegg S; Murdoch Children's Research Institute, Melbourne, Australia.; Department of Paediatrics, The University of Melbourne, Melbourne, Australia., Robevska G; Murdoch Children's Research Institute, Melbourne, Australia., Sinclair AH; Murdoch Children's Research Institute, Melbourne, Australia.; Department of Paediatrics, The University of Melbourne, Melbourne, Australia., Ayers KL; Murdoch Children's Research Institute, Melbourne, Australia.; Department of Paediatrics, The University of Melbourne, Melbourne, Australia., Dias-da-Silva MR; Laboratory of Molecular and Translational Endocrinology (LEMT), Endocrinology Division, Department of Medicine, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil. mrdsilva@unifesp.br. |
المصدر: | Cell & bioscience [Cell Biosci] 2024 Jan 04; Vol. 14 (1), pp. 3. Date of Electronic Publication: 2024 Jan 04. |
نوع المنشور: | Journal Article |
اللغة: | English |
بيانات الدورية: | Publisher: BioMed Central Country of Publication: England NLM ID: 101561195 Publication Model: Electronic Cited Medium: Print ISSN: 2045-3701 (Print) Linking ISSN: 20453701 NLM ISO Abbreviation: Cell Biosci Subsets: PubMed not MEDLINE |
أسماء مطبوعة: | Original Publication: London : BioMed Central, 2011- |
مستخلص: | Background: The absence of expression of the Y-chromosome linked testis-determining gene SRY in early supporting gonadal cells (ESGC) leads bipotential gonads into ovarian development. However, genetic variants in NR2F2, encoding three isoforms of the transcription factor COUP-TFII, represent a novel cause of SRY-negative 46,XX testicular/ovotesticular differences of sex development (T/OT-DSD). Thus, we hypothesized that COUP-TFII is part of the ovarian developmental network. COUP-TFII is known to be expressed in interstitial/mesenchymal cells giving rise to steroidogenic cells in fetal gonads, however its expression and function in ESGCs have yet to be explored. Results: By differentiating induced pluripotent stem cells into bipotential gonad-like cells in vitro and by analyzing single cell RNA-sequencing datasets of human fetal gonads, we identified that NR2F2 expression is highly upregulated during bipotential gonad development along with markers of bipotential state. NR2F2 expression was detected in early cell populations that precede the steroidogenic cell emergence and that retain a multipotent state in the undifferentiated gonad. The ESGCs differentiating into fetal Sertoli cells lost NR2F2 expression, whereas pre-granulosa cells remained NR2F2-positive. When examining the NR2F2 transcript variants individually, we demonstrated that the canonical isoform A, disrupted by frameshift variants previously reported in 46,XX T/OT-DSD patients, is nearly 1000-fold more highly expressed than other isoforms in bipotential gonad-like cells. To investigate the genetic network under COUP-TFII regulation in human gonadal cell context, we generated a NR2F2 knockout (KO) in the human granulosa-like cell line COV434 and studied NR2F2-KO COV434 cell transcriptome. NR2F2 ablation downregulated markers of ESGC and pre-granulosa cells. NR2F2-KO COV434 cells lost the enrichment for female-supporting gonadal progenitor and acquired gene signatures more similar to gonadal interstitial cells. Conclusions: Our findings suggest that COUP-TFII has a role in maintaining a multipotent state necessary for commitment to the ovarian development. We propose that COUP-TFII regulates cell fate during gonad development and impairment of its function may disrupt the transcriptional plasticity of ESGCs. During early gonad development, disruption of ESGC plasticity may drive them into commitment to the testicular pathway, as observed in 46,XX OT-DSD patients with NR2F2 haploinsufficiency. (© 2023. The Author(s).) |
References: | J Cell Sci. 2013 Jul 1;126(Pt 13):2834-44. (PMID: 23613466) Front Endocrinol (Lausanne). 2023 Jan 04;13:1086276. (PMID: 36686449) Arterioscler Thromb Vasc Biol. 2012 Nov;32(11):e135-46. (PMID: 22962329) Nat Rev Endocrinol. 2014 Nov;10(11):673-83. (PMID: 25246082) Nature. 2022 Jul;607(7919):540-547. (PMID: 35794482) Nat Commun. 2023 Apr 4;14(1):1867. (PMID: 37015919) Bioinformatics. 2013 Jan 1;29(1):15-21. (PMID: 23104886) Gynecol Oncol. 2021 Feb;160(2):568-578. (PMID: 33328126) Nucleic Acids Res. 2022 Jul 5;50(W1):W782-W790. (PMID: 35610053) Cancers (Basel). 2011 Feb 18;3(1):700-15. (PMID: 24212637) Stem Cell Reports. 2020 Dec 8;15(6):1377-1391. (PMID: 33217324) Cells. 2019 Dec 31;9(1):. (PMID: 31906104) Nucleic Acids Res. 2022 Jul 5;50(W1):W216-W221. (PMID: 35325185) Endocr Rev. 2019 Aug 1;40(4):857-905. (PMID: 30590466) Environ Toxicol. 2018 Feb;33(2):209-219. (PMID: 29139221) Biochem J. 2013 Jun 1;452(2):345-57. (PMID: 23458092) Science. 2017 Aug 18;357(6352):717-720. (PMID: 28818950) Elife. 2023 Feb 21;12:. (PMID: 36803359) Eur J Hum Genet. 2023 Oct;31(10):1117-1124. (PMID: 37500725) Nat Protoc. 2009;4(1):44-57. (PMID: 19131956) Int J Mol Sci. 2019 Dec 03;20(23):. (PMID: 31816857) EMBO J. 2011 Jan 19;30(2):237-48. (PMID: 21151097) Biomolecules. 2023 Apr 19;13(4):. (PMID: 37189438) Genome Biol. 2014;15(12):550. (PMID: 25516281) Dev Biol. 2001 Dec 1;240(1):92-107. (PMID: 11784049) J Endocrinol. 2014 Jun;221(3):R145-61. (PMID: 24741072) Database (Oxford). 2016 May 02;2016:. (PMID: 27141089) Mol Endocrinol. 2005 Sep;19(9):2299-308. (PMID: 15890675) Dev Dyn. 2004 Jun;230(2):210-5. (PMID: 15162500) Nat Protoc. 2008;3(6):1101-8. (PMID: 18546601) Cell Rep. 2019 Mar 19;26(12):3272-3283.e3. (PMID: 30893600) Int J Cancer. 1993 Feb 20;53(4):613-20. (PMID: 8436435) Genes Dev. 1999 Apr 15;13(8):1037-49. (PMID: 10215630) Mol Endocrinol. 2012 Aug;26(8):1268-77. (PMID: 22734039) Clin Endocrinol (Oxf). 2021 Apr;94(4):667-676. (PMID: 33296530) Nucleic Acids Res. 2018 Jul 2;46(W1):W242-W245. (PMID: 29762716) Bioinformatics. 2016 Oct 1;32(19):3047-8. (PMID: 27312411) Nucleic Acids Res. 2019 May 7;47(8):e47. (PMID: 30783653) BMC Bioinformatics. 2012 Jun 18;13:134. (PMID: 22708584) Cell Stem Cell. 2017 Jun 1;20(6):858-873.e4. (PMID: 28457750) Andrology. 2022 Oct;10(7):1411-1425. (PMID: 35973717) Nat Rev Urol. 2023 Jul;20(7):434-451. (PMID: 37020056) J Endocr Soc. 2019 Aug 28;3(11):2107-2113. (PMID: 31687637) Int J Mol Sci. 2022 Jul 06;23(14):. (PMID: 35886859) PLoS One. 2012;7(5):e37064. (PMID: 22615892) Mol Endocrinol. 1998 Jul;12(7):1010-22. (PMID: 9658405) Reproduction. 2022 Jun 27;164(2):31-40. (PMID: 35666805) Arq Bras Endocrinol Metabol. 2012 Dec;56(9):618-26. (PMID: 23329184) Am J Hum Genet. 2014 Apr 3;94(4):574-85. (PMID: 24702954) Cell Rep. 2018 Feb 6;22(6):1589-1599. (PMID: 29425512) Am J Hum Genet. 2018 Mar 1;102(3):487-493. (PMID: 29478779) Hum Reprod. 2017 Aug 1;32(8):1751-1760. (PMID: 28854582) Proc Natl Acad Sci U S A. 2007 Apr 10;104(15):6293-8. (PMID: 17404209) Nucleic Acids Res. 2015 Dec 2;43(21):e140. (PMID: 26184878) Proc Natl Acad Sci U S A. 2015 Mar 31;112(13):4003-8. (PMID: 25775596) Cell Stem Cell. 2021 Apr 1;28(4):764-778.e4. (PMID: 33453151) Nat Protoc. 2013 Nov;8(11):2281-2308. (PMID: 24157548) PLoS One. 2008 Sep 26;3(9):e3285. (PMID: 18818749) Horm Res Paediatr. 2023;96(2):180-189. (PMID: 34469891) Mod Pathol. 2010 Nov;23(11):1477-85. (PMID: 20693978) J Biotechnol. 2019 Aug 10;301:11-17. (PMID: 31158411) Front Endocrinol (Lausanne). 2022 Apr 07;13:881309. (PMID: 35464056) Cell Mol Life Sci. 2022 Sep 17;79(10):522. (PMID: 36114905) Dev Biol. 2014 Oct 15;394(2):242-52. (PMID: 25158167) |
معلومات مُعتمدة: | 2021/00684-3 Fundação de Amparo à Pesquisa do Estado de São Paulo; 200262/2022-0 Conselho Nacional de Desenvolvimento Científico e Tecnológico |
فهرسة مساهمة: | Keywords: 46,XX DSD; Bipotential gonad; COUP-TFII; Sex development; Supporting gonadal cells |
تواريخ الأحداث: | Date Created: 20240104 Latest Revision: 20240108 |
رمز التحديث: | 20240108 |
مُعرف محوري في PubMed: | PMC10768475 |
DOI: | 10.1186/s13578-023-01182-5 |
PMID: | 38178246 |
قاعدة البيانات: | MEDLINE |
تدمد: | 2045-3701 |
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DOI: | 10.1186/s13578-023-01182-5 |