Characterising novel pathways in testis determination using mouse genetics

Abstract

Mammalian sex determination is the process by which the bipotential embryonic genital ridge commits to either the testicular or ovarian fate. The existence of a gonad primordium with 2 possible developmental outcomes, depending on the presence or absence of the Y chromosome, remains a fascinating paradigm for examining the manner in which genes cooperate to establish cell fate and regulate differentiation. Development of the mouse gonad offers a unique model for the investigation of sex determination, characterised by powerful transgenic, genomic and other experimental resources for the study of the molecular control of organogenesis. This review focuses on recent progress in our understanding of mouse testis determination, with an emphasis on multi-locus studies of mutant alleles aimed at constructing pathways of interacting gene products. Studies in 2 broad areas have been especially revealing: (i) identification of pathways required for the appropriate expression of Sry, and (ii) characterisation of the antagonistic interactions between the core testis- (SRY-SOX9-FGF9) and ovary- (RSPO1-WNT4-CTNNB1-FOXL2) determining gene regulatory networks. We discuss these advances with an eye on emerging themes in mammalian sex determination.