PROLIFERATIVE VS MEIOTIC FATE DECISION IN C. ELEGANS

描述（由申请人提供）：组织是由干细胞形成和维持的，干细胞可以产生进行自我更新增殖的子细胞和分化的子细胞。在自我更新/增殖的命运和分化的命运之间做出选择的机制在任何系统中都没有得到很好的理解。然而，打乱这个决定会导致干细胞丢失，导致组织衰竭，并导致癌症。我们的长期目标是了解秀丽隐杆线虫生殖系中增殖与分化的决定是如何做出的。秀丽隐杆线虫的生殖系是存在大量干细胞通过对称分裂进行分裂和分化的组织的主要模式系统，相比之下，更广泛研究的系统只有少量干细胞通过不对称分裂进行分化。GLP-1 Notch信号通路诱导生殖细胞增殖命运并抑制促进减数分裂细胞命运的三个冗余通路：GLD-1通路，其作用于翻译抑制；GLD-2通路，参与翻译激活；第三种途径通过基因分析揭示了其存在，但迄今为止还没有发现基因产物。哺乳动物的Notch信号在干细胞自我更新和致癌Notch激活中也很重要。项目目标解决该领域未解决的主要问题，包括：(1)确定增殖区群体是否仅由干细胞或干细胞和近端转运扩增细胞组成。(2)确定GLP-1信号在增殖命运中的转录靶点，并确定与三种减数分裂进入途径的调控关系。(3)鉴定翻译抑制促进减数分裂进入的GLD-1靶点。

DESCRIPTION (provided by applicant): Tissues are formed and maintained by stem cells that produce both daughters that undergo self-renewing proliferation and daughters that differentiate. The mechanisms by which the choice between the self-renewal/ proliferative fate and the differentiated fate are made are not well understood in any system. However, disruption of the decision can cause stem cell loss, resulting tissue depletion, and lead to cancer. Our long-term goal is to understand how the proliferation vs. differentiation decision is made in the C. elegans germline. The C. elegans germline is the major model system for tissues where there are a larger number of stem cells that divide and differentiate through symmetric divisions, in contrast to the more widely studied systems with a small number of stem cells and differentiation through asymmetric division. The GLP-1 Notch signaling pathway induces the germ cell proliferative fate and represses three redundant pathways that promote the meiotic cell fate: the GLD-1 pathway, which acts in translational repression; the GLD-2 pathway, which acts in translational activation; and a third pathway whose existence has been revealed through genetic analysis but no gene products have been identified to date. Notch signaling in mammals is also important in stem cell self-renewal and oncogenic Notch activation can lead to cancer. Project goals address major unanswered questions in the field and include: (1) Determining whether the proliferative zone population is composed of only stem cells or both stem cells and proximal transit amplifying cells. (2) Identifying transcriptional targets of GLP-1 signaling for the proliferative fate and determining regulatory relationships with the three meiotic entry pathways. (3) Identifying the GLD-1 targets that are translationally repressed to promote meiotic entry.