The Molecular Action and Regulation of the Testis-Determining Factors, SRY (Sex-Determining Region on the Y Chromosome) and SOX9 [SRY-Related High-Mobility Group (HMG) Box 9]

Despite 12 yr since the discovery of SRY, little is known at the molecular level about how SRY and the SRY-related protein, SOX9 [SRY-related high-mobility group (HMG) box 9], initiate the program of gene expression required to commit the bipotential embryonic gonad to develop into a testis rather than an ovary. Analysis of SRY and SOX9 clinical mutant proteins and XX mice transgenic for testis-determining genes have provided some insight into their normal functions. SRY and SOX9 contain an HMG domain, a DNA-binding motif. The HMG domain plays a central role, being highly conserved between species and the site of nearly all missense mutations causing XY gonadal dysgenesis. SRY and SOX9 are architectural tran-scription factors; their HMG domain is capable of directing nuclear import and DNA bending. Whether SRY and SOX9 activate testis-forming genes, repress ovary-forming genes, or both remains speculative until downstream DNA target genes are identified. However, factors that control SRY and SOX9 gene expression have been identified, as have a dozen sexdetermining genes, allowing some of the pieces in this molecular genetic puzzle to be connected. Many genes, however, remain unidentified, because in the majority of cases of XY females and in all cases of XX males lacking SRY, the mutated gene is unknown. (Endocrine Reviews 24: 466 -487, 2003) I. Introduction and Historical Review II. SRY, the Testis-Determining Factor A. The discovery of SRY B. Gonadal expression of SRY C. The SRY protein D. Clinical mutations in SRY E. DNA binding activity of SRY from an XY female F. SRY: activator or repressor? G. The SRY HMG box: all you need? H. In vivo targets of SRY I. SRY-interacting proteins III. SOX9, the Campomelic Dysplasia/Autosomal Sex-Reversal Gene A. The discovery of SOX9 B. Clinical mutations in SOX9 C. SOX9 protein structure and activity D. SOX9 function in gonad and bone formation IV. Regulation of SRY Expression in the Developing Gonad A. SRY promoter analysis B. Regulation of SRY transcription by SF1 and SP1 C. Regulation of SRY transcription by WT1 V. Regulation of SOX9 Expression in the Developing Gonad VI. Initiating Sex Determination: A Molecular Genetic Model VII.