Genetic Analyses of Dendrite Development in Caenorhabditis elegans

秀丽隐杆线虫树突发育的遗传分析

• 批准号: 9239433
• 负责人: Hannes Erich Buelow
• 金额: $ 36.53万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9239433
• 关键词: Aging; Animal Model; Axon; Behavior; Biochemical; Biological Models; Biological Process; Bipolar Neuron; CCL4 gene; Caenorhabditis elegans; Candidate Disease Gene; Cell Adhesion Molecules; Cell Death; Cell Shape; Cells; Complex; Cues; Defect; Dendrites; Development; Extracellular Matrix Proteins; Extracellular Protein; Extracellular Space; Genes; Genetic; Genetic Screening; Guanine Nucleotide Exchange Factors; Guanine Nucleotides; Learning; Leucine; Leucine-Rich Repeat; Mediating; Mental Retardation; Mitogen-Activated Protein Kinases; Molecular Genetics; Morphogenesis; Morphology; Names; Nematoda; Neural Cell Adhesion Molecule L1; Neurodevelopmental Disorder; Neurons; Organism; Output; Pathway interactions; Pattern; Process; Proprotein Convertases; Proteins; Proteomics; Publishing; Research; Shapes; Signal Pathway; Signal Transduction; Signaling Molecule; Skin; Structure; Sum; Synapses; Translating; Work; autism spectrum disorder; axon guidance; chemokine; design; genetic analysis; human disease; in vivo; mutant; neural circuit; neurodevelopment; neuropsychiatric disorder; novel; programs; receptor; relating to nervous system; somatosensory; transmission process

PI: Buelow, Hannes E. Project Summary Behavior in multicellular organisms is controlled by neural circuits, which consist of interconnected neurons that integrate synaptic input, and compute output. Most neurons are bipolar and comprise dendrites and axons, which mediate reception and transmission of information, respectively. Dendrite branching is necessary for correct circuit assembly. While great strides have been made to understand axon development and branching, less is known about dendrite development. We are using the pair of PVD and FLP neurons in the small nematode C. elegans to investigate basic genetic and molecular mechanisms of dendrite development. Both PVD and FLP neurons elaborate highly branched dendritic arbors that employ conserved mechanisms during dendrite development. In a genetic screen for loci required for the formation of the stereotypic dendritic arbors of PVD neurons, we retrieved mutants with defects in PVD dendrite morphogenesis. Analyses of several of these genes identified the `menorin' pathway. This pathway is comprised of the conserved novel cell adhesion molecule MNR-1/menorin that acts in a complex with the adhesion molecule SAX-7/L1CAM from the skin through a leucine rich transmembrane receptor on PVD dendrites. In addition, we have found that the proprotein convertase kpc-1/furin acts genetically in the menorin pathway and that catalytic activity is required in PVD for patterning different aspects of dendritic arbor development. This proposal is aimed at two basic questions that arise from our published and unpublished studies. First, what are the in vivo targets of the proprotein convertase KPC-1/furin during these processes? Second, what may be the signaling pathway(s) operating within the PVD (or FLP) neurons? In the first aim we will define and characterize in vivo targets of the proprotein convertase kpc-1/furin that we have identified by a combination of proteomics and a candidate gene approach. In a second aim we will analyze the function of a novel extracellular protein, which has not previously been implicated in PVD dendrite development and which also appears to act in the `menorin' pathway. In a third aim, we will conduct a phenotypic, genetic and molecular characterization of an intracellular signaling molecule, which acts in PVD within the menorin pathway and likely downstream of the DMA-1 transmembrane receptor. In sum, our studies are aimed at a better understanding of basic aspects of dendrite development by focusing on non-autonomous mechanisms that in conjunction with a novel pathway pattern development of somatosensory dendrites.

PI：Buelow，Hannes E. 项目概要 多细胞生物的行为由神经回路控制，神经回路由相互连接的 整合突触输入并计算输出的神经元。大多数神经元是双极的，包括 树突和轴突，分别介导信息的接收和传输。枝晶 分支对于正确的电路组装是必要的。虽然已经取得了长足的进步 了解轴突发育和分支，但对树突发育了解较少。我们是 使用小型线虫秀丽隐杆线虫中的一对 PVD ​​和 FLP 神经元来研究基本遗传 和树突发育的分子机制。 PVD 和 FLP 神经元都高度精细 在树突发育过程中采用保守机制的分支树突乔木。在一个 对形成 PVD ​​神经元定型树突状乔木所需的基因座进行遗传筛选， 我们检索到了PVD树突形态发生有缺陷的突变体。对这几个方面的分析 基因识别出“menorin”途径。该途径由保守的新细胞组成 粘附分子 MNR-1/menorin 与粘附分子 SAX-7/L1CAM 形成复合物 从皮肤通过 PVD ​​树突上富含亮氨酸的跨膜受体。此外，我们还有 发现前蛋白转化酶 kpc-1/furin 在 menorin 通路中发挥遗传作用，并且 PVD 需要催化活性才能形成树突乔木发育的不同方面。 该提案针对我们已发表和未发表的研究中出现的两个基本问题。 首先，前蛋白转化酶 KPC-1/弗林蛋白酶在这些过程中的体内靶标是什么？ 其次，PVD（或 FLP）神经元内运行的信号通路可能是什么？在 第一个目标是，我们将定义并表征前蛋白转化酶 kpc-1/furin 的体内靶标， 我们通过蛋白质组学和候选基因方法的结合进行了鉴定。在第二个目标中 我们将分析一种新的细胞外蛋白的功能，该蛋白以前从未被涉及过 参与 PVD ​​树突发育，并且似乎也在“menorin”途径中发挥作用。在第三个目标中， 我们将对细胞内信号传导进行表型、遗传和分子表征 分子，在 Menorin 通路内的 PVD ​​中起作用，并且可能在 DMA-1 的下游 跨膜受体。总之，我们的研究旨在更好地理解基本方面 通过关注非自主机制与新颖的结合来实现树突的发育 体感树突的途径模式发育。