Molecular and genetic events in mammalian sex determination and differentiation

The molecular and genetic events in mammalian sex determination and differentiation. The bipotential genital ridge is established by several genes including NR5A1 [Wilhelm, et al, 2007; Sekido and Lovell-Badge, 2009]. In the XY gonad the activation of SRY expression, possibly initiated by GATA4/FOG2/NR5A1/WT1, leads to the upregulation of SOX9 expression via a synergy with NR5A1 [Sekido and Lovell-Badge 2008, 2009]. In the XX gonad, the supporting cell precursors accumulate β-catenin in response to RSPO1/WNT4 signalling and repress SOX9 activity [Schlessinger, et al, 2010]. Once SOX9 levels reach a critical threshold, several positive regulatory loops are initiated, including autoregulation of its own expression and formation of feed-forward loops via FGF9 or PGD2 signalling [Sekido and Lovell-Badge, 2009]. At later stages, FOXL2 may repress SOX9 expression [Uhlenhaut, et al, 2009]. In the testis, SOX9 promotes the testis pathway, including AMH activation, and it also probably represses the ovarian genes WNT4 and FOXL2 [Sekido and Lovell-Badge, 2009; Uhlenhaut, et al, 2009; Schlessinger, et al, 2010]. DMRT1 controls sex determination in some species of fish and may be the master sex-determining switch in birds, but its role in mammalian sexual development is unclear [Wilhelm, et al, 2007; Smith, et al, 2009]. Much of this data has been generated from studies in mice.