The SRY gene product, SRY, is detected in the bipotential gonad of XY individuals at about 42 days. The protein contains an HMG (high mobility group) box of 79 amino acids that binds to specific regions of DNA, causing the DNA molecule to bend. This bending is thought to make these regions more accessible to other transcription-regulating proteins which ultimately bring about the differentiation of the gonadal cells, some to Sertoli cells, some to Leydig cells. SRY also contains nuclear localization signals, phosphorylation sites, and additional protein–protein interaction sites.
As depicted in Figure 1, a major transcription factor in testicular development is SOX9 an autosomal gene regulated by the SRY protein. In XY fetus, SOX9 is also positively regulated by FGF9 and the product of prostaglandin D synthase, PGD2 (see Chapter 8). SOX9 also has its own positive feedback loop. Sustained elevated lev els of SOX9 lead to normal development of the testes. Since the gene for SOX9 is autosomal, it can also be expressed in XX fetuses and adults. Its expression and consequent inappropriate development of testicular cells in the XX fetus is restrained by the Wnt4/β catenin signaling pathway. This brake on SOX9 expression is required for maintenance of normal ovarian function in the female throughout reproductive life and this is provided by FOXL2 (Forkhead box L2), among other factors.
Fig1. Signaling pathways in the control of gonad differentiation. In the XY fetus, SRY (sex determining region of the Y chromosome) activates the expression of SOX9 (SRY-related HMG-box-9; HMG=high mobility group), a potent transcription factor that is required for the expression of the proteins required for fetal testis differentiation. FGF9 (fibroblast growth factor 9) and prostaglandin D2 (produced by PGDS = prostaglandin D synthase) also contribute to the maintenance of SOX9 expression in the male. In the embryonic female SOX9 expression is suppressed by the WNT4/β-catenin pathway and its stimulators. In the adult female, normal ovarian function requires the continued suppression of SOX9, which is mediated by the transcription factor FOXL2 (Forkhead box L2).
By the end of the sixth week after conception the Sertoli cells of the fetal testis have begun to differentiate and secrete anti-Müllerian hormone (see below). Within the next two weeks, the Leydig cells appear and begin to secrete testosterone. Ovarian differentiation follows that of the testis by 4–5 weeks.
