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

描述(申请人提供)：控制生殖系中干细胞群体的细胞增殖是生物系统的一个基本属性，需要一个精致的 监管水平，以确保正常的生殖功能。多细胞生物体的有性繁殖取决于许多生殖细胞，这些生殖细胞决定是分化还是继续分裂(减数分裂与有丝分裂)。细胞增殖的调节可能需要一些外部信号，如营养或应激条件，这可能会影响增殖能力的调节，这是细胞命运指定的一个鲜为人知的方面，以及有丝分裂的调节和细胞周期的控制。线虫生殖系是研究生殖细胞增殖的遗传、发育和环境控制的有价值的模型。由于生长控制的基本性质，它的调控很可能通过进化得到保守，从而能够使用简单的、遗传上易驯化的生物作为模型系统。一个保守的GLP-1/Notch信号通路控制着细胞的命运，是保持增殖能力还是通过进入减数分裂进行分化。在这项研究中，我们将阐明自噬和其他内吞途径在GLP-1/Notch信号转导中的作用。具体地说，我们的建议旨在：(1)确定自噬和逆转录活性在线虫发育过程中的作用，特别是在GLP-1/Notch信号在生殖系发育中的调节中的作用，以及(2)阐明内吞基因在自噬小体的形成、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有机体发育和控制细胞增殖中作用的机制的理解。 它们将提供有关发育过程中需要自噬的组织和信号通路中涉及的蛋白质的信息。我们的实验室凭借我们在线虫遗传学和自噬研究方面的专业知识，在开展这一项目方面具有得天独厚的优势。 公共卫生相关性：本研究旨在通过检测自噬、逆转录功能和Notch/GLP-1信号通路之间的联系，探讨自噬在生殖系发育中的作用。

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.