Sex determination and fertility
- 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 XX embryos, the stabilization of ovarian differentiation is secured by the WNT/b-catenin signalling pathway mediated by R-spondin1 and by the transcription factor, FOXL2. Our lab has just shown that one isoform of WT1 is essential to initiate ovarian development as described in https://www.science.org/stoken/author-tokens/ST-1527/full . However, the knowledge on mechanisms governing sex determination is still fragmented and consequently about 50% of gonadal dysgenesis remains unexplained in humans.
Understanding sex determination or how two completely different organs, the testis or the ovary, 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 and in turn male development. In XX gonads, the progenitor cells maintain Rspo1 expression after entering the gonads. We have identified that -KTS isoform of WT1 is the long-sought ovarian determinant and induces the differentiation of the progenitor cells into granulosa cells, the somatic cells that will form the ovarian follicles after birth. Next, Rspo1 is required for embryonic granulosa cell maintenance during embryogenesis. Mutations in these key factors triggers gonadal dysgenesis ranging from streak gonad to sex reversal. To address these questions, we combine genetic, molecular and genomic approaches.
Testis development is determined by the activation of SRY and SOX9. Around the same time, the down-regulation of RSPO1/WNT/b-catenin signalling is critical for the differentiation of this organ. There are still many questions that need to be answered in order to understand testis development, such as why a limited number of cells become supporting cells or steroidogenic cells, how RSPO1/WNT/b-catenin signalling is down-regulated, etc.
In XX gonads, the -KTS isoform of WT1 induces ovarian differentiation and Rspo1 is necessary to sustain the ovarian fate, but there are still fundamental questions to be answered, such as how the cell populations of the ovary are specified, how RSPO1 protects the ovary from reprogramming as ovotestis, etc. Understanding the normal role of this pathway is a prerequisite for the study of ovarian pathogenesis.
The gonad is the site of germ cells differentiation. 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 elucidated.
Our team is dedicated to trying to answer some of these questions. These findings will lead to better understanding of some of the many cases of gonadal dysgenesis and cancers that have yet to find an explanation.
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- 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.
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- 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