Sex determination in mice
- Sex determination in mammals
- Normal and pathogenic development of the gonad
- Ovarian homeostasis and repair
- WNT/b-catenin signalling and Sox genes
In mammals, the pivotal decision to develop as male or female begins with the differentiation of the bipotential gonad allowing the development of two highly specialized organs: the testis or the ovary. This will condition the whole sexual fate of the individual. At a molecular level, sex determination depends on two antagonistic molecular pathways. The SRY gene located on the Y chromosome initiates testicular development by up-regulating the transcription factor SOX9 in XY embryos. In contrast, ovarian differentiation requires up-regulation of the secreted proteins RSPO1 and WNT4 in XX embryos. Eventually, the dominant pathway will determine the sex of the individual. However, the knowledge on mechanisms governing sex determination is still fragmented and consequently about 50% of gonadal dysgenesis remains unexplained in humans. Our aim is to unravelling these mechanisms involved in normal and pathologic development of testes and ovaries.
Understanding sex determination or how two completely different organs, the ovary or the testis, differentiate from the same precursor is a unique quest in biology. We have a long-standing interest in the processes driving sex determination, sexual differentiation, and gonad homeostasis. We have shown that Rspo1 promotes progenitor cell proliferation in the bipotential gonad. After their ingression into the gonads, cells in the XY gonads stop expressing Rspo1 and activate the testis determining genes Sry and Sox9. We have shown that Sox9 is required for the differentiation of Sertoli cells, the supporting cells of the testis. Indeed, mutations in this gene cause male-to-female sex reversal. In XX gonads, the progenitor cells maintain Rspo1 expression after entering the gonads. They differentiate as granulosa cells, the somatic cells that will form the ovarian follicles after birth. We have shown that Rspo1 is required for fetal granulosa cell maintenance during embryogenesis. Accelerated differentiation of this cell population is associated with female-to-male sex reversal. To address these questions, we combine genetic, molecular and genomic approaches. Our current aim is to deepen our knowledge of sex differentiation and maintenance of the sexual fate. We also aim to identify new players in these processes, especially factors likely to be involved in disorders of sexual development and other pathologies like ovarian cancers in humans.
Testis differentiation is determined by the paternal transmission of the SRY gene, which is required for SOX9 up-regulation. However many facts about male determination are still unknown such as why only a subset of cells express SRY and what are other cellular and molecular mechanims involved in testis differentiation. One of our goals is to understand at a cellular and molecular level how gonadal differentiation tiltes towards the testicular fate.
In XX gonads, we have shown that Rspo1 is necessary for the female fate, but we do not yet know how this process is initiated and the role of Rspo1. Rspo1 regulates WNT/b-catenin signalling, a critical pathway also implicated in folliculogenesis and ovarian homeostasis. Understanding the normal role of this pathway is a prerequisite for the study of ovarian pathogenesis.
In addition to determining the sex of the individual, the gonad is also the site of germ cells differentiation to insure the propagation of species. It is now clear that the fate of the gonad and germ cells are closely linked and the exact cellular and molecular mechanism governing sex-specific germ cell differentiation remain to be known.
- Le Rolle, M, Massa, F, Siggers, P, Turchi, L, Loubat, A, Koo, BK et al.. Arrest of WNT/β-catenin signaling enables the transition from pluripotent to differentiated germ cells in mouse ovaries. Proc Natl Acad Sci U S A. 2021;118 (30):. doi: 10.1073/pnas.2023376118. PubMed PMID:34301885 PubMed Central PMC8325354.
- Mayère, C, Neirijnck, Y, Sararols, P, Rands, CM, Stévant, I, Kühne, F et al.. Single-cell transcriptomics reveal temporal dynamics of critical regulators of germ cell fate during mouse sex determination. FASEB J. 2021;35 (4):e21452. doi: 10.1096/fj.202002420R. PubMed PMID:33749946 .
- Chassot, AA, Le Rolle, M, Jolivet, G, Stevant, I, Guigonis, JM, Da Silva, F et al.. Retinoic acid synthesis by ALDH1A proteins is dispensable for meiosis initiation in the mouse fetal ovary. Sci Adv. 2020;6 (21):eaaz1261. doi: 10.1126/sciadv.aaz1261. PubMed PMID:32494737 PubMed Central PMC7244317.
- Richardson, N, Gillot, I, Gregoire, EP, Youssef, SA, de Rooij, D, de Bruin, A et al.. Sox8 and Sox9 act redundantly for ovarian-to-testicular fate reprogramming in the absence of R-spondin1 in mouse sex reversals. Elife. 2020;9 :. doi: 10.7554/eLife.53972. PubMed PMID:32450947 PubMed Central PMC7250573.
- Tang, F, Richardson, N, Albina, A, Chaboissier, MC, Perea-Gomez, A. Mouse Gonad Development in the Absence of the Pro-Ovary Factor WNT4 and the Pro-Testis Factor SOX9. Cells. 2020;9 (5):. doi: 10.3390/cells9051103. PubMed PMID:32365547 PubMed Central PMC7291083.
- De Cian, MC, Gregoire, EP, Le Rolle, M, Lachambre, S, Mondin, M, Bell, S et al.. R-spondin2 signaling is required for oocyte-driven intercellular communication and follicular growth. Cell Death Differ. 2020;27 (10):2856-2871. doi: 10.1038/s41418-020-0547-7. PubMed PMID:32341451 PubMed Central PMC7493947.
- Vidal, VP, Jian-Motamedi, F, Rekima, S, Gregoire, EP, Szenker-Ravi, E, Leushacke, M et al.. R-spondin signalling is essential for the maintenance and differentiation of mouse nephron progenitors. Elife. 2020;9 :. doi: 10.7554/eLife.53895. PubMed PMID:32324134 PubMed Central PMC7228766.
- Grabek, A, Dolfi, B, Klein, B, Jian-Motamedi, F, Chaboissier, MC, Schedl, A et al.. The Adult Adrenal Cortex Undergoes Rapid Tissue Renewal in a Sex-Specific Manner. Cell Stem Cell. 2019;25 (2):290-296.e2. doi: 10.1016/j.stem.2019.04.012. PubMed PMID:31104943 .
- Stévant, I, Kühne, F, Greenfield, A, Chaboissier, MC, Dermitzakis, ET, Nef, S et al.. Dissecting Cell Lineage Specification and Sex Fate Determination in Gonadal Somatic Cells Using Single-Cell Transcriptomics. Cell Rep. 2019;26 (12):3272-3283.e3. doi: 10.1016/j.celrep.2019.02.069. PubMed PMID:30893600 .
- Gregoire, EP, Stevant, I, Chassot, AA, Martin, L, Lachambre, S, Mondin, M et al.. NRG1 signalling regulates the establishment of Sertoli cell stock in the mouse testis. Mol Cell Endocrinol. 2018;478 :17-31. doi: 10.1016/j.mce.2018.07.004. PubMed PMID:30040984 .
- Chassot, AA, Le Rolle, M, Jourden, M, Taketo, MM, Ghyselinck, NB, Chaboissier, MC et al.. Constitutive WNT/CTNNB1 activation triggers spermatogonial stem cell proliferation and germ cell depletion. Dev Biol. 2017;426 (1):17-27. doi: 10.1016/j.ydbio.2017.04.010. PubMed PMID:28456466 .
- Minkina, A, Lindeman, RE, Gearhart, MD, Chassot, AA, Chaboissier, MC, Ghyselinck, NB et al.. Retinoic acid signaling is dispensable for somatic development and function in the mammalian ovary. Dev Biol. 2017;424 (2):208-220. doi: 10.1016/j.ydbio.2017.02.015. PubMed PMID:28274610 PubMed Central PMC5411265.
- Lacour, F, Vezin, E, Bentzinger, CF, Sincennes, MC, Giordani, L, Ferry, A et al.. R-spondin1 Controls Muscle Cell Fusion through Dual Regulation of Antagonistic Wnt Signaling Pathways. Cell Rep. 2017;18 (10):2320-2330. doi: 10.1016/j.celrep.2017.02.036. PubMed PMID:28273449 PubMed Central PMC5357729.
- Pannetier, M, Chassot, AA, Chaboissier, MC, Pailhoux, E. Involvement of FOXL2 and RSPO1 in Ovarian Determination, Development, and Maintenance in Mammals. Sex Dev. 2016;10 (4):167-184. doi: 10.1159/000448667. PubMed PMID:27649556 .
- Biason-Lauber, A, Chaboissier, MC. Ovarian development and disease: The known and the unexpected. Semin Cell Dev Biol. 2015;45 :59-67. doi: 10.1016/j.semcdb.2015.10.021. PubMed PMID:26481972 .
- Bandiera, R, Sacco, S, Vidal, VP, Chaboissier, MC, Schedl, A. Steroidogenic organ development and homeostasis: A WT1-centric view. Mol Cell Endocrinol. 2015;408 :145-55. doi: 10.1016/j.mce.2015.01.009. PubMed PMID:25596547 .
- Chassot, AA, Gillot, I, Chaboissier, MC. R-spondin1, WNT4, and the CTNNB1 signaling pathway: strict control over ovarian differentiation. Reproduction. 2014;148 (6):R97-110. doi: 10.1530/REP-14-0177. PubMed PMID:25187620 .
- Rastetter, RH, Bernard, P, Palmer, JS, Chassot, AA, Chen, H, Western, PS et al.. Marker genes identify three somatic cell types in the fetal mouse ovary. Dev Biol. 2014;394 (2):242-52. doi: 10.1016/j.ydbio.2014.08.013. PubMed PMID:25158167 .
- Chahal, JK, Wong, VS, Chaboissier, MC, Brubaker, PL. R-spondin1 deficiency enhances β-Cell neogenesis in a murine model of diabetes. Pancreas. 2014;43 (1):93-102. doi: 10.1097/MPA.0b013e3182a70bfb. PubMed PMID:24263108 .
- Maatouk, DM, Mork, L, Chassot, AA, Chaboissier, MC, Capel, B. Disruption of mitotic arrest precedes precocious differentiation and transdifferentiation of pregranulosa cells in the perinatal Wnt4 mutant ovary. Dev Biol. 2013;383 (2):295-306. doi: 10.1016/j.ydbio.2013.08.026. PubMed PMID:24036309 PubMed Central PMC4066978.
- De Cian M.C., Pauper E., Bandiera R., Vidal V.P.I., Sacco S., Gregoire E.P., Chassot A.A., Panzolini C., Wilhelm D., Pailhoux E., Youssef S.A., de Bruin A., Teerds K., Schedl A., Gillot I. and Chaboissier M.C. (2017). Amplification of R-spondin1 signaling induces granulosa cell fate defects and cancers in mouse adult ovary. Oncogene 36(2):208-218. PMID: 27270435
iBV - Institut de Biologie Valrose
"Centre de Biochimie"
Université Nice Sophia Antipolis
Faculté des Sciences
06108 Nice cedex 2