Figure 1. Summary of the molecular events in sex determination indicating the genes in which molecular defects can cause gonadal disorders in animal models. Some of these disorders were confirmed in humans. Nr5a1, Wnt4 and Wt1 are expressed in the urogenital ridge whose development results in formation of the gonads, kidneys, and adrenal cortex. Several genes, Wt1, Nr5a1, M33 (CBX2 mouse homologue), Lhx9, Lim1, Gata4/Fog2, Dmrt1, Emx2 and Cited are expressed in the bipotential gonad. Nr5a1 up-regulates Cbx2 expression that is required for upregulation of the Sry gene. Nr5a1 and Wt1 up-regulate Sry expression in pre-Sertoli cells and Sry initiates male gonad development. Sry strongly up-regulates Sox9 in Sertoli cells. Sox9 up-regulates Fgf9 and Fgf9 maintains Sox9 expression, forming a positive feed-forward loop in XY gonads. The balance between Fgf9 and Rspo1/Wnt4 signals is shifted in favor of Fgf9, establishing the male pathway. If Wnt4/Rspo1 is overexpressed activating the β-catenin pathway, this system blocks Fgf9 and disrupts the feed-forward loop between Sox9 and Fgf9. Pdg2 signaling up-regulates Sox9 and Sox9 activate Ptgds. Sox9 establishes a feed-forward loop with the Pgd2. Sox9 inhibits beta-catenin-mediated Wnt signaling. Overexpression in either Dax1 (locus DSS) or Rspo1/Wnt4 antagonizes testis formation. On the other hand, Dax1 regulates the development of peritubular myoid cells and the formation of testicular cords. Dmrt1 has recently been shown to be required for the maintenance of gonadal sex and to prevent female reprogramming in postnatal testis, Cbx2 directly or indirectly repress ovarian development. Dhx37 has critical roles in early human testis determination and also in the maintenance of testicular tissue.