Elucidation of the regulatory mechanisms of spermatogonial stem cell fate

点击翻译按钮获取中文摘要

This NSERC Discovery Grant is intended to support a fundamental research program aiming to discover cellular mechanisms that regulate spermatogonial stem cell (SSC) fate. SSCs form a small subpopulation of cells in the mammalian testis and represent the progenitor population of all germ cells. Compared to other stem cell types in the organism, SSCs are unique, since they are dispensable for the individual but crucial for survival of the species. SSCs can be directed toward one of two cell fate decisions: either differentiation into more specialized germ cells that will eventually become spermatozoa, or self-renewal. The proper regulation of SSCs is critical for spermatogenesis and malfunction in the process of differentiation and/or proliferation of SSCs will cause problems ranging from infertility to tumor formation. A handful of recent studies performed by myself and others demonstrated that members of a family of signaling molecules called WNTs (wingless-related mouse mammary tumor virus integration site) are expressed by Sertoli cells; a cell type essential to nourish the developing germ cells through all the stages of spermatogenesis. These studies also suggested that WNTs may play major roles in both normal and pathological SSC fate. In spite of these studies, knowledge of the physiological role of WNTs secreted by Sertoli cells remains highly limited. Therefore, my laboratory will explore in detail the role of WNTs produced by Sertoli cells on SSC commitment to self-renewal. The objectives of my laboratory are: 1) to study the physiological role of WNTs secreted by Sertoli cells in vivo, 2) to determine the mechanism of delivery of WNTs from Sertoli cells to SSCs, and 3) to identify downstream transcriptional targets of the WNT/JNK pathway in SSCs. Taken together, these studies will unravel novel regulatory mechanisms involved in fundamental aspects of testicular physiology, and will further our understanding of stem/progenitor cell biology, spermatogenesis and infertility across the mammalian spectrum. Potential applications of this research proposal include the use of SSCs as a method of preserving endangered species; as a novel technique to generate transgenic animal models or; as a source of pluripotent cells in regenerative medicine. This new knowledge will represent a key contribution to an important research field that is currently understudied in Canada.