Genetic Analyses of Dendrite Development in Caenorhabditis elegans

派：Buelow，Hannes E. 项目摘要 多细胞生物体的行为是由神经回路控制的，神经回路由相互连接的 整合突触输入和计算输出的神经元。大多数神经元是双极的，包括 树突和轴突，分别调节信息的接收和传递。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，对树突发育知之甚少。我们是 利用小线虫PVD和FLP神经元对的基础遗传学研究 枝晶发育的分子机制。PVD和FLP神经元都高度复杂 树枝状乔木，在树枝发育过程中采用保守机制。在一个 对形成PVD神经元典型树突所需的基因座进行遗传筛选， 我们回收了PVD树突形态发生缺陷的突变体。对其中几个问题的分析 基因确定了“月经”途径。这条途径由保守的新细胞组成 与黏附分子SAX-7/L1CAM形成复合体的黏附分子MNR-1/Menorin 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 发现原蛋白转换酶KPC-1/Furin在薄荷素途径中发挥遗传作用，并且 在PVD中需要催化活性来构图树枝发育的不同方面。 这项建议是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，在这些过程中，原蛋白转换酶KPC-1/Furin的体内靶点是什么？ 第二，PVD(或FLP)神经元内的信号通路(S)可能是什么？在 首先，我们将定义和表征原蛋白转换酶KPC-1/Furin的体内靶标 我们已经通过蛋白质组学和候选基因方法的组合来鉴定。在第二个目标中 我们将分析一种新的胞外蛋白的功能，这是以前没有涉及到的 在PVD树突状细胞的发育中，它似乎也在“月经”途径中起作用。第三个目标是， 我们将对一种细胞内信号进行表型、遗传学和分子表征。 分子，作用于薄荷素途径中的PVD，可能位于DMA-1的下游 跨膜受体。总而言之，我们的研究旨在更好地了解 通过关注非自治机制来发展树枝晶，与新的 体感树突的通路模式发展。

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 This proposal is aimed at two basic questions that arise from our published and unpublished studies.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.