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: 9327082
• 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/9327082
• 关键词: Aging; Animal Model; Axon; Behavior; Biochemical; Biological Models; Biological Process; Bipolar Neuron; Caenorhabditis elegans; Candidate Disease Gene; Cell Adhesion Molecules; Cell Death; Cells; Complex; Cues; Defect; Dendrites; Development; Diffuse; Extracellular Matrix Proteins; Extracellular Protein; Extracellular Space; Genes; Genetic; Genetic Screening; Guanine Nucleotide Exchange Factors; Guanine Nucleotides; Instruction; Leucine; Leucine-Rich Repeat; Mediating; Mental Retardation; Mitogen-Activated Protein Kinases; Molecular; Molecular Genetics; Morphogenesis; Morphology; Names; Nematoda; Neural Cell Adhesion Molecule L1; Neurodevelopmental Disorder; Neurons; Organism; Output; Pathologic; Pathway interactions; Pattern; Phenotype; 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; neuroregulation; novel; permissiveness; 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. 项目摘要 多细胞生物中的行为由神经回路控制，这些电路由互连 整合突触输入并计算输出的神经元。大多数神经元是双极性的，包括 树突和轴突，分别介导信息的接收和传播。树突 分支对于正确的电路组件是必需的。虽然已经取得了长足的进步 了解轴突的发育和分支，对树突的发展知之甚少。我们是 在小线虫C.秀丽隐杆线虫中使用一对PVD和FLP神经元来研究基本遗传 和树突发展的分子机制。 PVD和FLP神经元都高度详细说明 在树突发展过程中采用保守机制的树枝状树枝状轴。在 形成PVD神经元的刻板印象树突轴所需的基因座的遗传筛查， 我们检索了PVD树突形态发生中缺陷的突变体。其中几个的分析 基因确定了“甲素蛋白”途径。该途径由保守的新细胞组成 与粘附分子SAX-7/L1CAM作用在复合物中的粘附分子MNR-1/脑膜 从皮肤穿过PVD树突上富含亮氨酸的跨膜受体。此外，我们还有 发现普罗蛋白转化酶KPC-1/Furin在甲诺蛋白途径中起作用，并且 PVD中需要催化活性来模仿树突状植树发育的不同方面。 该提案针对我们发表和未发表的研究引起的两个基本问题。 首先，在这些过程中，普罗蛋白转化酶KPC-1/Furin的体内靶标是什么？ 其次，在PVD（或FLP）神经元内运行的信号通路可能是什么？在 我们将定义和表征前蛋白转化酶KPC-1/furin的体内靶标的第一个目标 我们通过蛋白质组学和候选基因方法的结合来确定。在第二个目标 我们将分析一种新型细胞外蛋白的功能，以前尚未暗示 在PVD树突开发中，它似乎也表现在“ Menorin”途径中。在第三个目标中 我们将进行细胞内信号传导的表型，遗传和分子表征 分子，该分子在Menorin途径内作用于PVD，并且可能是DMA-1的下游 跨膜受体。总而言之，我们的研究旨在更好地理解 树枝状发育是通过关注与新颖的非自主机制的关注 体感树突的途径模式发展。