Mammalian sex determination occurs during a short period in embryonic development, with SRY (Sex determining Region on the Y chromosome) playing a key role. In the 1940s, Jost et al. demonstrated that a testis is necessary for development of the male phenotype in mammals, as implied by the fact that castrated rabbits of either chromosomal sex developed as females (Jost et al. 1973). Karyotypes of patients with Turner Syndrome (45, X) and Klinefelter syndrome (47, XXY) demonstrated that sex is chromosomally controlled, and that the Y chromosome, in particular, determines male development regardless of X chromosome number (Vilain and McCabe 1998). Based on these observations, it was hypothesized that a dominant inducer of testis formation, the so-called testis determination factor (TDF), was located on the Y chromosome and encoded a gene or genes specifying the male phenotype; in...
SRY plays a key role in mammalian sex determination with mutations in Sry resulting in sex reversal. Since its discovery several decades ago, slow progress has been made in determining the mechanisms of SRY function. Lack of experimental systems, especially in humans, has limited the study of sex determination to the mouse, with further limitations due to the brief period of expression of Sry in a small number of embryonic cells. It is clear however, that upregulation of SOX9 by SRY is a key event in mediating male sex differentiation, with emerging evidence implicating a role for SRY in repressing ovarian development through Wnt/ß-catenin. Significantly, the dual nuclear import mechanisms of SRY play a key role in male sex determination, with mutations therein resulting in impaired SRY targeting to the nucleus and sex reversal. Intriguingly, calcium plays a role in switching between the two import mechanisms of SRY to enable efficient SRY nuclear accumulation to be maintained under various physiological conditions. A key to understanding the development of the male sex will be in unraveling the regulation of Sry expression in early gonadal development, the dynamic movements of SRY within the cell during its brief period of expression, and the interplay of key sex determining proteins leading to repressed ovarian function and favored testis development.
- Assumpcao JG, Benedetti CE, Maciel-Guerra AT, Guerra Jr G, Baptista MT, Scolfaro MR, et al. Novel mutations affecting SRY DNA-binding activity: the HMG box N65H associated with 46, XY pure gonadal dysgenesis and the familial non-HMG box R30I associated with variable phenotypes. J Mol Med. 2002;80(12):782–90.PubMedPubMedCentralCrossRefGoogle Scholar