RESEARCH: Transcriptional Regulation of Mammalian Spermatogenesis The ability of each cell to selectively express a distinct set of genes under specific external stimuli is central to cellular differentiation and organogenesis, and a loss of this ability leads to diseases such as cancer. My laboratory utilizes mammalian spermatogenesis as a model system for cellular differentiation and seeks to understand the mechanisms involved in cell-specific gene transcription. Sperm, unlike other cells in the human body, contain very unique structures such as the acrosome and the flagellum and the expression of genes encoding the acrosomal and flagellar proteins signals the terminal differentiation of male germ cells. One goal in the laboratory is to identify the master transcription factors responsible for spermatid-specific gene expression. A second goal is to understand the mechanisms which prevent the expression of the spermatid-specific genes in somatic tissues. Using transgenic mice as a model organism and the gene encoding the acrosomal protein SP-10 as a model gene, we gained some insights into the regulation of spermatid-specific gene expression and identified TDP-43, PURalpha and Musashi as transcription factors important for this process. Our work also identified an insulator with enhancer-blocking properties, which likely plays a role in preventing the expression of the spermatid-specific SP-10 gene in somatic tissues. Currently, we are focusing on understanding the biology of TDP-43, PURalpha and Musashi proteins in the testis and the mechanism by which they orchestrate spermatid-specific gene expression. Interestingly, aberrant expression of these proteins has been shown to be associated with certain types of cancer, indicating their critical roles in normal cellular function. The outcome of these studies will contribute to a better understanding of mammalian spermatogenesis at the molecular level and will have clinical significance. Today, the incidence of infertility is about 15% and in greater than 80% of male infertility cases, the cause of infertility is unknown (idiopathic). We anticipate that our studies will lead to a better prognosis of male infertility. Further, regulatory factors, which are critical for the completion of spermatogenesis, offer potential targets for the development of novel male contraceptives. Publications:
|
