In the mouse, SOX9 is expressed at low levels in the bipotential gonads of both sexes under SF1 regulation 95but persists only in testicular Sertoli cells after SRY expression has peaked 96 - SRY and SF1 directly bind to several sites within a 3. In fact, overexpression of SOX9 during early embryogenesis induces testicular differentiation in two different models of transgenic XX mice Functional analysis of SOX9 during sex determination, by conditional gene targeting in mice, has shown that homozygous deletion of Sox9 in XY gonads interferes with sex cord development and with activation of testis specific markers Further evidence for the role of SOX9 in testicular development comes from observations in humans, in whom a double dose of SOX9 expression is required. Heterozygous mutations result in haploinsufficiency resulting in campomelic dysplasia, a polymalformative syndrome that includes sex-reversal due to gonadal dysgenesis in XY individuals 93, whereas gain-of-function of SOX9 in XX individuals leads to sex reversal In humans more distant regulatory regions of SOX9 have been identifiedand confirmed by observations in patients with XY gonadal dysgenesis. No mutation has been found in the TES sequenceinstead a 1.
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