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Wnt/β-catenin, SOX signaling & sex determination
Summary
While male and female gonadal development have been considered as independent, sex determination is regulated by opposing signals, (XY) tipped toward maleness by the presence of SRY. In females R-Spondin 1 (a Wnt agonist) is the earliest driving force. Using cell and molecular biology techniques, this project aims to understand the mechanisms of action of these two opposing pathways.
Description
Gonadogenesis is a highly regulated process in which the bipotential gonad has the ability to develop in either testis or ovary. The fate of the undifferentiated bipotential gonad is genetically controlled by the sex chromosomes constitution of an individual, XY for male and XX for females.
In XY individuals, the expression in the supporting cell lineage, of a single gene on the Y-chromosome, SRY, is essential to determine the fate of the bipotential gonad toward testis differentiation.
While male and female gonadal development have been considered in the past as independent pathways, our preliminary results and recent studies in mice have indicated that sex determination is regulated by opposite signals, and that the balance between male and female signals is ultimately tipped toward maleness by the presence of SRY expression.
Strong evidences indicate that R-Spondin 1 (an agonist of the Wnt/b-catenin pathway) is the earliest driving force of the female pathway whereas SRY/SOX9 pathway is the primary driving force of the male pathway.
Until now, little is known about how these two pathway interact with each other and how they can inhibit each other. Our project aim to understand the mechanisms of action of these two opposite pathways involved in the formation of either a testis or an ovary.
Funding
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National Health and Medical Research Council
Selected Publications
Bernard, P., Ryan, J., Sim, H., Czech, D.P., Sinclair, A.H., Koopman, P. and Harley, V.R. (2012) Wnt signaling in ovarian development inhibits Sf1 activation of Sox9 via the Tesco enhancer. Endocrinology 153: 901-912
Bernard, P. and Harley, V.R. (2010) Acquisition of SOX transcription factor specificity through protein-protein interaction, modulation of Wnt signalling and post-translational modification. International Journal of Biochemistry and Cell Biology 42: 400-410