Opposing Pathways in Mammalian Sex Determination

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DESCRIPTION (provided by applicant): The gonad forms as a bipotential primordium that can develop into a testis or an ovary. As it develops it reveals the remarkable plasticity of cell fate and the finely balanced signaling mechanisms that compete to establish the male or female pathway. A Y-linked gene, Sry, controls male sex determination by initiating both Sertoli cell fate determination and the morphological organization of testis cords. In the past decade, much has been learned about downstream pathways that regulate testis morphogenesis. However, little is known about how Sry initiates this process. Available data suggests that transient expression of Sry controls a cell fate decision in Sertoli cell precursors that leads to the stable expression of Sox9 throughout the Sertoli lineage. Coincident with this process, Sertoli precursors begin to aggregate around germ cells, epithelialize, and undergo a process of de novo cord formation. Our hypothesis is that the fate determination step and the mesenchymal to epithelial transition of Sertoli precursor cells are molecularly linked through stabilized expression of SOX9. Investigation of this hypothesis will be the broad direction of our work during this funding period with emphasis on four main areas of focus. (1) Based on our previous work, we will use a lineage tracing approach to investigate how Sertoli precursors arise and activate Sox9 expression. (2) We have recently found molecular evidence for the competition of antagonistic pathways during Sertoli fate determination. Using mouse mutants, we will investigate how opposing signaling pathways and transcriptional networks result in the activation of the male pathway and the repression of the female pathway. (3) We plan to determine how the polycomb group chromatin remodeling protein, M33, is involved in the establishment of ovarian or testis developmental pathways using chromatin immunoprecipitation assays and M33 mutant mice. (4) We will investigate how testis cords form, and whether cord formation is linked to Sertoli cell differentiation through an interaction between SOX9 and MAP genes using live imaging, chimeric mice, markers of cell polarity and cell adhesion, and mice carrying mutations in cMaf and Mafb, members of a family shown to be critical for gonadogenesis in Drosophila, and known to interact with SOX9 during chondrogenesis in mammals.