During gestation, the cells of the primordial gonad that lie along the urogenital ridge are in a bipotential state, meaning they possess the ability to become either male cells (Sertoli and Leydig cells) or female cells (follicle cells and theca cells).<unk>  initiates<unk>  differentiation by activating male-specific transcription<unk> s that allow these bipotential cells to differentiate and proliferate.<unk>  accomplishes this by upregulating SOX9, a transcription<unk>  with a DNA-binding site very similar to<unk> 's. SOX9 leads to the upregulation of fibroblast growth<unk>  9 (Fgf9), which in turn leads to further upregulation of SOX9. Once proper SOX9 levels are reached, the bipotential cells of the gonad begin to differentiate into Sertoli cells. Additionally, cells expressing<unk>  will continue to proliferate to form the primordial<unk> . While this constitutes the basic series of events, this brief review should be taken with caution since there are many more<unk> s that influence sex differentiation. Action in the nucleus The<unk>  protein consists of three main regions. The central region encompasses the HMG (high-mobility group) domain, which contains nuclear localization sequences and acts as the DNA-binding domain. The C-terminal domain has no conserved structure, and the N-terminal domain can be phosphorylated to enhance DNA-binding. The process begins with nuclear localization of<unk>  by acetylation of the nuclear localization signal regions, which allows for the binding of importin β and calmodulin to<unk> , facilitating its import into the nucleus. Once in the nucleus,<unk>  and SF1 (steroidogenic<unk>  1, another transcriptional regulator) complex and bind to TESCO<unk> -specific enhancer of Sox9 core), the<unk> -specific enhancer element of the Sox9 gene in Sertoli cell precursors, located upstream of the Sox9 gene transcription start site. Specifically, it is the HMG region of<unk>  that binds to the minor groove of the DNA target sequence, causing the DNA to bend and unwind. The establishment of this particular DNA "architecture" facilitates the transcription of the Sox9 gene. In the nucleus of Sertoli cells, SOX9 directly targets the Amh gene as well as the prostaglandin D synthase (Ptgds) gene. SOX9 binding to the enhancer near the Amh promoter allows for the synthesis of Amh while SOX9 binding to the Ptgds gene allows for the production of prostaglandin D2 (PGD2). The reentry of SOX9 into the nucleus is facilitated by autocrine or paracrine signaling conducted by PGD2. SOX9 protein then initiates a positive feedback loop, involving SOX9 acting as its own transcription<unk>  and resulting in the synthesis of large amounts of SOX9. SOX9 and<unk>  differentiation The SF1 protein, on its own, leads to minimal transcription of the SOX9 gene in both the XX and XY bipotential gonadal cells along the urogenital ridge. However, binding of the<unk> -SF1 complex to the<unk> -specific enhancer (TESCO) on SOX9 leads to significant up-regulation of the gene in only the XY gonad, while transcription in the XX gonad remains negligible. Part of this up-regulation is accomplished by SOX9 itself through a positive feedback loop; like<unk> , SOX9 complexes with SF1 and binds to the TESCO enhancer, leading to further expression of SOX9 in the XY gonad. Two other proteins, FGF9 (fibroblast growth<unk>  9) and PDG2 (prostaglandin D2), also maintain this up-regulation. Although their exact pathways are not fully understood, they have been proven to be essential for the continued expression of SOX9 at the levels necessary for<unk>  development. SOX9 and<unk>  are believed to be responsible for the cell-autonomous differentiation of supporting cell precursors in the gonads into Sertoli cells, the beginning of<unk>  development. These initial Sertoli cells, in the center of the gonad, are hypothesized to be the starting point for a wave of FGF9 that spreads throughout the developing XY gonad, leading to further differentiation of Sertoli cells via the up-regulation of SOX9. SOX9 and<unk>  are also believed to be responsible for many of the later processes of<unk>  development (such as Leydig cell differentiation, sex cord formation, and formation of<unk> -specific vasculature), although exact mechanisms remain unclear. It has been shown, however, that SOX9, in the presence of PDG2, acts directly on Amh (encoding anti-Müllerian hormone) and is capable of inducing<unk>  formation in XX mice gonads, indicating it's vital to<unk>  development.
Testis-determining factor
Cenegermin
Androgen-binding protein
Core binding factor
Androgen prohormone
Dieldrin
Keratinocyte growth factor
Transfer factor