Role of autophagy and retromer genes in GLP-1/Notch signaling

描述（由申请人提供）：控制生殖系中细胞的干细胞群的细胞增殖是生物系统的基本性质，其需要精细的细胞学和生物学方法。 调节水平，以确保正常的生殖功能。多细胞生物的有性生殖取决于决定是否分化或继续分裂（减数分裂与有丝分裂）的生殖细胞的数量。细胞增殖的调节可能需要许多外部信号，如营养或应激条件，这可能影响增殖能力的调节，这是细胞命运特化的一个知之甚少的方面，以及有丝分裂的调节和细胞周期的控制。梭线虫生殖系是研究生殖细胞增殖的遗传、发育和环境控制的重要模型。由于生长控制的基本性质，它的调节很可能通过进化而被保存，使得能够使用简单的、遗传上易处理的生物体作为模型系统。保守的GLP-1/Notch信号通路控制细胞命运决定，以保持增殖能力或通过进入减数分裂分化。在这项研究中，我们将阐明自噬和其他内吞途径对GLP-1/Notch信号转导的作用。具体而言，我们的建议旨在：（1）确定自噬和retromer活动在C。elegans发育，特别是在生殖系发育中glp-1/Notch信号传导的调节中，以及（2）阐明内吞基因在自噬体形成、Dauer发育和生殖系发育中的作用。这些研究意义重大，因为它们将促进我们对自噬在多细胞生物体发育和控制细胞增殖中发挥作用的机制的理解。 它们将提供有关发育中需要自噬的组织和参与信号通路的蛋白质的信息。我们的实验室是独特的定位，以追求这个项目与我们的专业知识，在C。elegans遗传学和自噬的研究。 公共卫生相关性：本研究旨在通过检查自噬，retromer功能和Notch/GLP-1信号通路之间的联系，探索自噬-细胞质成分回收的细胞途径-在种系发育中的作用。

DESCRIPTION (provided by applicant): The control of cell proliferation of stem cell population of cells in the germline is a fundamental property of biological systems that requires an exquisite level of regulation to ensure normal reproductive function. Sexual reproduction of multicellular organisms depends on a number of germ cells that decide whether to differentiate or to continue to divide (meiosis vs. mitosis). The regulation of cell proliferation may require a number of external signals, such as nutrition or stress conditions, which may impact on the regulation of the competence to proliferate, a poorly understood aspect of cell fate specification, as well as the regulation of mitosis and the control of the cell-cycle. The C. elegans germline is a valuable model to study the genetic, developmental, and environmental control of germ cell proliferation. Because of the fundamental nature of growth control, its regulation is likely to be conserved through evolution, enabling the use of simple, genetically tractable organisms as model systems. A conserved GLP-1/Notch signaling pathway controls the cell fate decision to retain proliferative competence or to differentiate by entering meiosis. In this study, we will elucidate the role of autophagy and other endocytic pathways on GLP-1/Notch signaling. Specifically, our proposal aims to: (1) define the role of autophagy and retromer activity during C. elegans development, specifically in the regulation of the glp-1/Notch signaling in the development of the germline, and to (2) elucidate the role of endocytic genes in the formation of an autophagosome, in dauer development and during germline development. These studies are significant because they will advance our understanding of the mechanisms by which autophagy functions in the development of a multicellular organism, and in the control of cell proliferation. They will be informative regarding both the tissues that require autophagy in development and the proteins involved in the signaling pathway. Our laboratory is uniquely positioned to pursue this project with our expertise in C. elegans genetics and the study of autophagy. PUBLIC HEALTH RELEVANCE: This study aims to explore the role of autophagy - a cellular pathway by which cytoplasmic components are recycled - in germline development by examining links between autophagy, retromer function and the Notch/GLP-1 signaling pathway.