The proposed research is designed to develop a better understanding of the mechanisms that control and maintain testis development, in particular the manner by which a specific class of transcription factors regulate this process. Emphasis is placed on the elucidation of the transcriptional control of Sertoli cell differentiation. Sertoli cells are the epithelial cells responsible for the onset of embryonic testis development and the maintenance of spermatogenesis in the adult testis. Preliminary research has demonstrated that a unique class of transcription factors, basic helix-loop-helix proteins (bHLH), appear to be involved in Sertoli cell differentiation and thus important for testis development. The hypothesis tested is that Sertoli cell basic helix-loop-helix proteins are essential in the transcriptional regulation of Sertoli cell differentiation and critical for normal testis development and function. More specifically that hormones and locally produced paracrine factors promote Sertoli cell differentiation through the expression of specific bHLH proteins at various stages of testis development Abnormal testis development and male infertility may in part be due to inappropriate transcriptional control of Sertoli cell differentiation involving these bBLH proteins. The experimental approach consists of the following specific aims. 1) Investigate the role of bHLH proteins in Sertoli cell differentiation. 2) Investigate the developmental regulation of Sertoli bHLH gene expression. 3) Investigate the physiological function of Sertoli bHLH proteins during testis development. The completion of these studies will provide insight into the transcriptional regulation of Sertoli cell differentiation during testis development. Sertoli cell differentiation is essential for embryonic, prepubertal, pubertal and adult testis development. Abnormal Sertoli cell differentiation can cause infertility and a number of birth defects. Inappropriate expression of Sertoli cell genes such as SRY and MIS results in defects such as sex reversal, ambiguous gonads, and vanishing testis. Male infertility will also in part be due to abnormal transcriptional regulation of Sertoli cell differentiation. Therefore, observations from the current proposal on transcriptional regulation of Sertoli cell differentiation will provide a better understanding of normal and abnormal testis development and function.
