Genetic analysis of nematode cell differentiation

线虫细胞分化的遗传分析

• 批准号: 9902460
• 负责人: MARTIN CHALFIE
• 金额: $ 76.81万
• 依托单位: COLUMBIA UNIV NEW YORK MORNINGSIDE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-14 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9902460
• 关键词: Acetyltransferase; Address; Affect; Behavior; Biological Process; Caenorhabditis elegans; Cell Differentiation process; Cells; Cellular Mechanotransduction; Development; Disease; Epigenetic Process; Focal Adhesions; Generations; Genes; Goals; Guanosine Triphosphate Phosphohydrolases; HOX protein; Health; Human; Individual; Integrins; Knowledge; Lethal Genes; Maintenance; Mammals; Mechanics; Microtubules; Molecular Chaperones; Motor Neurons; Nematoda; Neuronal Differentiation; Neurons; Neuropeptides; Process; Proteins; Public Health; Research; Role; Specific qualifier value; Structure; Testing; Touch sensation; Translating; Translational Research; Tubulin; WNT Signaling Pathway; Work; cell type; genetic analysis; genetic approach; insight; novel; receptor; stoichiometry; transcription factor

Project Summary We will continue our study of genes needed for neuronal differentiation and function using the six touch receptor neurons (TRNs) of the nematode Caenorhabditis elegans. Our previous research identified genes needed for the generation, specification, maintenance and function of the TRNs. In the last few years we 1) identified genes needed for the specification of neuronal subtypes; 2) discovered a new activity of transcription factors, including Hox proteins (as “guarantors”) that maintains transcription factor expression by the restricting its stochastic expression; 3) examined the how the release of epigenetic inhibition affects the terminal differentiation of subtypes of motor neurons; 4) discovered several behaviors that modulate TRN touch sensitivity, including a previous unstudied type – long-term sensitization – and the mechanisms underlying these modulations; 5) identified a role for integrins and other focal adhesion proteins in neuronal mechanosensation; 6) discovered that the -tubulin acetyltransferase MEC-17 specifies the unusual, 15-protofilament structure of TRN microtubules; 7) discovered a new type of chaperone for the mechanosensory transduction channel; 8) determined the stoichiometry (MEC-42MEC-10) of the transduction channel; and 9) investigated the roles of the Wnt signaling pathway, Rac GTPases, and GEFs in process outgrowth. The general goal of the research going forward is to exploit these findings to understand how the differentiation of individual cell types is controlled and how mechanical inputs are sensed and modified. We plan to discover and characterize genes needed for TRN differentiation, specifically those needed for the differences among TRNs and TRN process outgrowth and ensheathment and to investigate touch sensitivity and its control by investigating newly identified lethal genes needed for touch sensitivity by testing and characterizing TRN-expressed genes for supersensitivity, and by studying the role of neuropeptides. The health relatedness of our work comes from the discovery of new genes and new interactions among genes that are similar in humans and other mammals.

项目摘要 我们将继续研究神经元分化所需的基因， 使用线虫的六个触觉受体神经元（TRN）的功能 优美的我们之前的研究确定了这一代所需的基因， TRN的规格、维护和功能。在过去的几年里，我们（1） 确定了神经元亚型特异性所需的基因; 2）发现了一种新的 转录因子的活性，包括Hox蛋白（作为“转录因子”）， 通过限制转录因子的随机表达来抑制转录因子的表达; 3）检测 表观遗传抑制的释放如何影响终末分化， 运动神经元的亚型; 4）发现了几种调节TRN触摸的行为 敏感性，包括以前未研究的类型-长期致敏-和 这些调节的机制; 5）确定了整合素和其他 神经元机械感觉中的粘着斑蛋白; 6）发现β-微管蛋白 乙酰转移酶MEC-17指定TRN的不寻常的15-原丝结构 微管; 7）发现了一种新型的机械感觉伴侣 转导通道; 8）确定了转导通道的化学计量（MEC-42 MEC-10）。 9）研究了Wnt信号通路、Rac 全球技术转让协定和全球环境基金的进程成果。研究的总体目标是 下一步是利用这些发现来了解单个细胞的分化 控制类型以及如何感测和修改机械输入。我们计划 发现和表征TRN分化所需的基因，特别是那些 TRN和TRN过程的生长和包被之间的差异所需的 并通过研究新发现的致命性， 通过测试和表征TRN表达的基因， 以及研究神经肽的作用。健康相关性 我们工作的一部分来自于发现新的基因和基因间的新的相互作用 与人类和其他哺乳动物相似的基因。