FIGURE 10.

SRY-regulated testicular differentiation and transcriptional activation of Sox9. A, central dogma of SRY-SOX9-driven male-specific gene regulatory network. Genetic interactions during male sex determination: the SRY-SOX9 pathway (red box) is essential for testis formation. SRY binds to upstream enhancer elements of Sox9 (5). These factors each act within a supporting cell lineage to direct Sertoli cell differentiation and signal to the other lineages (such as the Leydig cell pathway; vertical dotted line in center). Shown in schematic form are repressive pathways (⊥; oblique dashed and solid lines), which ensure that the central SRY pathway (horizontal at top) does not promote growth and differentiation of female primordial. This panel is adapted from Ref. 59 (with permission of the authors) with updated information (6). The abbreviations used are as follows: BMP8b, bone morphogenetic protein 8B; DAX1, dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1; DMRT1, double-sex and mab-3 related transcription factor 1; FGF9, fibroblast growth factor 9; GATA4, GATA-binding protein 4; LHX9, LIM homeobox 9; LIM1, homeobox protein Lhx 1; MIS, Müllerian inhibiting substance (also designated AMH, anti-Müllerian hormone); PTGDS, prostaglandin D₂ synthase; SF1, steroidogenic factor 1; WT1, Wilms tumor 1; Wnt, wingless-type murine mammary tumor virus integration site family, member 4. B, transient-transfection transcriptional assays in a rat embryogenic gonadal cell line: left to right, empty-vector control (open bar), wild-type (wt) SRY (black), V60L (green), V60A (red), and de novo controls R133W and I68T (gray). Histogram provides results of real time RT-PCR assays in CH34 cells; error bars indicate standard deviation of eight replicates. Results indicate that V60L and V60A SRY exhibit partial activity, whereas de novo mutations I68T and R133W essentially abolish Sox9 transcriptional activation (40). Statistical significance is indicated by asterisks as follows: * indicates p < 0.05; ** indicates p < 0.01.