PROLIFERATIVE VS MEIOTIC FATE DECISION IN C. ELEGANS

描述（由申请人提供）：组织由干细胞形成和维持，干细胞产生进行自我更新增殖的子细胞和分化的子细胞。在任何系统中，在自我更新/增殖命运和分化命运之间进行选择的机制都没有得到很好的理解。然而，破坏这一决定可能导致干细胞损失，导致组织耗竭，并导致癌症。我们的长期目标是了解C.秀丽隐杆线虫生殖系梭与具有少量干细胞和通过不对称分裂分化的更广泛研究的系统相反，线虫种系是组织的主要模型系统，其中存在大量通过对称分裂分裂和分化的干细胞。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条冗余通路：GLD-1通路，其在翻译抑制中起作用; GLD-2通路，其在翻译激活中起作用;以及第三条通路，其存在已通过遗传分析揭示，但迄今尚未鉴定出基因产物。哺乳动物中的Notch信号传导在干细胞自我更新中也是重要的，并且致癌Notch激活可导致癌症。该项目的目标是解决该领域尚未解决的主要问题，包括：（1）确定增殖区人群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信号传导的转录靶点，以促进增殖命运，并确定与三种减数分裂进入途径的调控关系。(3)鉴定被抑制以促进减数分裂进入的GLD-1靶标。 公共卫生相关性：拟议的研究调查了干细胞与分化决定，这是动物发育和成人组织稳态的重要组成部分。破坏这一决定可能导致干细胞损失，导致组织功能障碍，并可能导致癌症。

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. PUBLIC HEALTH RELEVANCE: The proposed research investigates the stem cell versus differentiation decision, which is an essential part of animal development and adult tissue homeostasis. Disruption of the decision can cause stem cell loss, resulting in tissue disfunction, and can lead to cancer.