Genetic Regulation of Mammalian Sexual Development

In most mammals, sex is determined by the presence or absence of the Y chromosome gene called Sry , for sex determining region of chromosome Y. Sry expression is sufficient for testis formation and its absence leads to ovary development. Sox9 is an Sry ‐box containing gene that is located on an autosome. Haploinsufficiency for Sox9 in humans and mice causes a lethal skeletal syndrome called captomelic dysplasia. The majority of human XY SOX9 heterozygous individuals also have abnormalities in sexual development (i.e. male to female sex reversal), indicating a role in testis formation. Sox9 is expressed in many tissues during development, including the XY genital ridge and gonad in immature and later in mature Sertoli cells. Transgenic Sox9 expression in developing XX gonads results in testis formation, demonstrating that Sox9 , like Sry , is also sufficient for testis formation. In contrast to humans, XY Sox9 +/− mice have normal appearing testes. The neonatal lethality of Sox9 +/− mice hinders the generation of homozygous mutants to determine the role of Sox9 in testis formation. A germ cell−specific knockout strategy has been used to efficiently generate Sox9 −/ − mice. Unfortunately, these mice die at 11.5 days post‐coitus (dpc) prior to testis differentiation that would occur at 12.5 dpc in wild‐type embryos. In vitro culture of 11.5 dpc genital ridges showed that XY Sox9 −/ − gonads do not differentiate into testes but rather assume an ovarian fate. These studies define Sox9 as an essential autosomal determinant for mammalian sexual development. Supported by NIH HD30284.