Elucidation of the regulatory mechanisms of spermatogonial stem cell fate

NSERC发现基金旨在支持一项基础研究计划，该计划旨在发现调节精原干细胞(SSC)命运的细胞机制。SSCs在哺乳动物的睾丸中形成一个小的细胞亚群，代表所有生殖细胞的祖细胞群体。与生物体中的其他干细胞类型相比，SSCs是独一无二的，因为它们对个体来说是必不可少的，但对物种的生存至关重要。SSCS可以决定两种细胞的命运：要么分化成更专业的生殖细胞，最终成为精子，要么自我更新。SSCs的正确调控对精子发生至关重要，SSCs在分化和/或增殖过程中的功能障碍将导致从不育到肿瘤形成等一系列问题。我和其他人最近进行的几项研究表明，被称为WNTs(无翅相关小鼠乳腺肿瘤病毒整合位点)的信号分子家族的成员由支持细胞表达；支持细胞是在精子发生的所有阶段为发育中的生殖细胞提供营养所必需的细胞类型。这些研究还表明，WNTs可能在正常和病理性SSC的命运中发挥重要作用。尽管有这些研究，但对支持细胞分泌的WNTs的生理作用的了解仍然非常有限。因此，我的实验室将详细探讨Sertoli细胞产生的WNTs在SSC自我更新承诺中的作用。本实验室的目标是：1)研究支持细胞分泌的WNTs在体内的生理作用；2)确定WNTs从Sertoli细胞向SSCs传递的机制；3)确定SSCs中WNT/JNK途径的下游转录靶点。综上所述，这些研究将揭开涉及睾丸生理学基本方面的新的调控机制，并将加深我们对哺乳动物范围内的干/祖细胞生物学、精子发生和不育的理解。这项研究建议的潜在应用包括使用SSCs作为保护濒危物种的方法；作为产生转基因动物模型的新技术；作为再生医学中多能细胞的来源。这一新知识将是对加拿大目前正在研究的一个重要研究领域的关键贡献。

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.