Transcriptional Determinants of Cell Differentiation

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Sperm are highly specialized cells and express numerous cell-specific mRNAs required for their proper development and function. Many of these mRNAs are generated from germ cell-specific genes or promoters, and numerous transcription factors are uniquely enriched in spermatogenic cells. However, extremely little is currently known about the role of individual transcription factors in directing male germ cell differentiation, including the specific gene targets they regulate and their mutual transcriptional interactions. The long-term goal of this proposal is to elucidate the transcriptional network responsible for elaboration of the spermatogenic differentiation program. A particular emphasis is the identification of spermatogenic cell-specific transcription factors required for the differentiation of meiotic spermatocytes and haploid spermatids. We recently identified a unique, male germ cell-enriched form of the transcription factor, SREBP2, which is required for cholesterol and energy metabolism in somatic cells. This factor, SREBP2gc, possesses several cell-specific properties which suggest novel, stage-dependent functions during spermatogenesis. It is our hypothesis that spermatogenic cells have adapted the ubiquitously expressed SREBP2 transcription factor to regulate a totally distinct set of novel, cell-specific target genes that are important for germ cell differentiation. Recent findings now demonstrate that SREBP2gc regulates the germ cell-specific proacrosin gene promoter. The aims of this proposal are: 1) to determine the impact of perturbing SREBP2gc function on sperm formation and function as well as on germ cell-specific gene expression; 2) further characterize the transcriptional interactions between SREBP2gc and the mouse proacrosin promoter; and 3) generate transgenic mice expressing epitope-tagged SREBP2gc. These mice will be used to further examine direct target genes for SREBP2gc during spermatogenesis. These studies will greatly advance our understanding of the transcriptional program underlying the formation of sperm, and may reveal underlying mechanisms important in male infertility and for the development of male contraceptives.