Genes involved in testicular development and function.

The development of the testis requires the highly regulated expression of a series of genes. Many of the genes involved are transcription factors, such as steroid hormone receptors and growth factors. Investigators have used gene cloning, mutation analysis, transgenic mice, and gene-deletion studies to define the role of specific genes in testicular development and function. In the past 5 years, investigators have defined a gene on the Y chromosome, SRY, thought to be required for testis determination. This protein is a member of a larger family of related transcription factors. Expression of this gene triggers a cascade of events that leads to the development of the Sertoli cell, Leydig cells, and the testis. The development of the male phenotype is dependent on the presence and action of androgens, which exert their effect after combining with a receptor in the nucleus of the target cell that stimulates gene transcription. Defects in the androgen receptor gene lead to a full spectrum of morphological defects in the male. Interestingly, mutations in other members of the steroid receptor superfamily, such as the estrogen receptor gene, also affect male fertility. A number of "orphan" receptors (i.e., receptors whose ligans have not been identified) are also required for normal testicular development and function, as are several genes normally thought to be tumor-suppressor genes (e.g., Wilms' tumor-suppressor gene). In contrast, alpha-inhibin has been thought to be an endocrine hormone, yet it functions as a tumor-suppressor gene in the testis. Testicular development and normal spermatogenesis require the proper function and coordination of a large number of transcription factors, steroid hormone and orphan receptors, and growth factors. There are likely to be a large number of other, as yet unidentified genes that are necessary for male gonadal development.