PROLIFERATIVE VS MEIOTIC FATE DECISION IN C. ELEGANS

描述(申请人提供)：组织由干细胞形成和维持，干细胞产生经历自我更新增殖的子代和分化的子代。在自我更新/扩散命运和分化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，决策的中断可能会导致干细胞丢失，导致组织枯竭，并导致癌症。我们的长期目标是了解线虫种系中增殖和分化的决定是如何做出的。线虫生殖系是组织的主要模式系统，在组织中有大量的干细胞通过对称分裂进行分裂和分化，而不是更广泛地研究的系统具有少量的干细胞和通过不对称分裂进行分化。GLP-1 Notch信号通路诱导生殖细胞的增殖命运，并抑制三条促进减数分裂细胞命运的冗余通路：GLD-1途径，作用于翻译抑制；GLD-2途径，作用于翻译激活；以及第三条途径，其存在的基因分析已被发现，但到目前为止还没有发现基因产物。哺乳动物中的Notch信号在干细胞自我更新过程中也很重要，致癌的Notch激活可能导致癌症。项目目标解决了该领域尚未回答的主要问题，包括：(1)确定增殖区群体是仅由干细胞组成，还是同时由干细胞和近端转运放大细胞组成。(2)确定GLP-1信号转导的转录靶点，并确定与三条减数分裂进入途径的调控关系。(3)识别翻译抑制的GLD-1靶点以促进减数分裂进入。

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.