Mammalian gonadal sex determination is a powerful system for studying organogenesis, cell fate determination, and the evolution of sex chromosomes and developmental regulatory mechanisms. Besides basic scientific interest, mammalian sex determination also is of biomedical interest. Approximately one in 1000 infants has a gonadal or genital anomaly. Furthermore, many of the known genes involved in sex determination also are implicated in pathological processes such as tumorigenesis and primary adrenal failure, and have essential roles in the normal development of organs other than the gonads. We use the mouse as a model system for studying mammalian sex determination and gonad organogenesis and employ genetic, molecular genetic, genomic, cell biological and embryological techniques.

In mammals, XY fetuses develop testes due to the action of the Y-linked testis determining gene Sry (sex-determining region, Y chromosome) and XX fetuses develop ovaries in its absence. SRY is a DNA binding protein, and is likely a transcription factor that regulates other genes in the sex determination pathway. The mammalian gonadal precursors (the genital ridges) are bipotential and capable of differentiating as either testes or ovaries. It is generally accepted that each genital ridge contains a complete set of lineage precursors that are capable of adopting an ovarian or testicular cell-type fate. This "common precursor" hypothesis is best viewed as a series of bipotential cell fate decisions within the four cell lineages that comprise the gonad: germ cells, connective tissue cells, steroid producing cells and supporting cells. The current model proposes that Sry expression in the genital ridge initiates testis development by directing supporting cell precursors to develop as Sertoli rather than granulosa cells and that the development of all other gonadal cell types is dependent on the differentiation of the supporting cell lineage. Besides Sertoli cell differentiation, two direct consequences of Sry expression are the initiation of a malespecific pattern of cell proliferation and the induction of mesenchymal cell migration from the adjacent mesonephros into the developing testis, a process necessary for testis cord development.

Our recent studies have contributed to our understanding of both sex determination and gonad organogenesis. For example, we have shown that Sry, the mammalian male sex determining gene, is expressed in preSertoli cells, and that Sertoli and granulosa cells develop from a common precursor. We also demonstrated that Sry is necessary and sufficient to induce male specific mesonephric cell migration into the developing gonad and showed that mesonephric cell migration is critical for normal testis development. Additionally, we have developed mouse models for human sex reversal that may help explain a number of unresolved sex reversal cases including XY females and XY hermaphrodites who carry an apparently normal SRY gene and XY females who carry a mutated SRY gene inherited from their father who carried the same mutated SRY allele. In short, our studies have demonstrated that Sry expression levels are critical for normal sex determination and are highly sensitive to genetic background. These studies have increased our understanding of the regulation of Sry expression and will lead to the identification of new genes in the sex determination and gonad differentiation pathways.

Although it is clear that expression of Sry is the trigger for testis differentiation, the molecular mechanisms of Sry function remain an enigma. For example, no downstream SRY target genes have been unequivocally identified and the regulation of Sry expression remains largely unexplored. A number of genes involved in gonadogenesis and sex determination have been identified and characterized; however, the position and relationship of these genes within the pathway remain to be defined and many more genes remain to be discovered. For example, most of the identified genes are transcription factors and not effector molecules. Additionally, our understanding of the genes involved in ovary development is particularly thin. Our future studies will include investigating the regulation of Sry expression, defining the position and relationship of known genes and identifying new genes in the gonad differentiation and sex determination pathways, and exploring basic mechanisms of gonad differentiation.