Elucidation of the regulatory mechanisms of spermatogonial stem cell fate

这项NSERC发现基金旨在支持一项基础研究计划，旨在发现调节精原干细胞（SSC）命运的细胞机制。精原干细胞在哺乳动物睾丸中形成一小部分细胞亚群，代表所有生殖细胞的祖细胞群。与生物体中的其他干细胞类型相比，SSC是独特的，因为它们对个体来说是必需的，但对物种的生存至关重要。精原干细胞可以被导向两种细胞命运决定之一：要么分化成最终成为精子的更特化的生殖细胞，要么自我更新。精原干细胞的适当调节对于精子发生至关重要，精原干细胞分化和/或增殖过程中的功能障碍将导致从不育到肿瘤形成的问题。我和其他人最近进行的一些研究表明，一个名为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;支持细胞是一种在精子发生的所有阶段滋养发育中的生殖细胞所必需的细胞类型。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，支持细胞分泌的WNTs的生理作用的知识仍然非常有限。因此，我的实验室将详细探索支持细胞产生的WNT对SSC自我更新承诺的作用。本实验室的目的是：1）研究支持细胞分泌的WNT在体内的生理作用，2）确定WNT从支持细胞到SSCs的传递机制，3）确定SSCs中WNT/JNK通路的下游转录靶点。总之，这些研究将揭示睾丸生理学基本方面的新的调控机制，并将进一步加深我们对干/祖细胞生物学、精子发生和哺乳动物不育的理解。这项研究提案的潜在应用包括使用SSCs作为保护濒危物种的方法;作为一种新的技术来生成转基因动物模型;或作为再生医学中多能细胞的来源。这一新知识将对加拿大目前研究不足的一个重要研究领域作出关键贡献。

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.