The role of nuclear receptors SF1 and DAX1 in the tenuous process of sex determination
Sex determination is governed by a series of genetic switches that influence cell fate and differentiation during gonadal development. Sex chromosomal composition (XX vs XY) is a critical determinant of phenotypic sex. The identification of the testis-determining gene, SRY (Sex-reversed on the Y) was a pivotal first step towards unraveling this genetic pathway. It is now clear that numerous other genes, in addition to SRY, are necessary for normal testis development. For example, human mutations in a variety of genes (SOX9, WT1, SF1) impair testis development. Murine models provide additional evidence for key genes (i.e., Wt1, Lhx9, Sry, Sox9. Sf1, Dmrt, Fgf9) in the testis determining pathway. This lecture will highlight insights gleaned from human mutations in the nuclear receptors, SF-1 (Steroidogenic factor-1) (NR5A1) and DAX-1 (Dosage-sensitive sex reversal, Adrenal hypoplasia congenital, X chromosome) (NR0B1). Mutations in DAX1 cause adrenal hypoplasia congenita (AHC), an X-linked disorder characterized by adrenal insufficiency and failure to undergo puberty because of hypogonadotropic hypogonadism. Targeted mutagenesis of Dax1 (Ahch) in mice reveals an additional role in testis development and spermatogenesis. Although initially suggested to function as an anti-testis gene, we have shown that Dax1 is necessary for normal testis development. The identification of naturally-occurring SF-1 mutations has revealed a spectrum of phenotypes ranging from adrenal insufficiency and XY sex reversal to isolated adrenal insufficiency or gonadal dysgenesis. These examples underscore the exquisite sensitivity of SF-1 dependent developmental pathways to gene dosage and function in humans. In addition to their clinical relevance, studies of SF1 and DAX1 are proving useful for defining the genetic pathways that govern adrenal and gonadal development.