Neuronal migration in C. elegans

描述(申请人提供)：神经元胞体和生长锥迁移塑造了神经系统的整体模式和连通性。这项拟议研究的目的是调查控制神经元迁移的机制。了解这些基本机制可以帮助我们深入了解如何修复受损的神经系统。该提案有三个具体目标。1)确定VAB-8和UNC-73三个同系物是如何调节导向受体的。大量的轴突轨迹是由一些保守的引导分子引导的。许多引导受体被广泛表达，这提出了一个问题，即神经元如何在特定的引导线索中进行选择，以启动和终止定向生长。我们发现，激动素相关分子VAB-8通过控制其在细胞表面的受体水平来调节对指导信号的敏感性，VAB-8通过保守的RAC全球环境基金UNC-73/Trio发挥作用。本研究的目的是证明UNC-73、VAB-8与导向受体SAX-3/RobO、UNC-5和UNC-40之间的物理相互作用介导了VAB-8对这些受体的作用，表明VAB-8的作用是通过RAC信号途径实现的，并确定了促进这些受体在细胞表面聚集的机制。2)确定WNT信号、VAB-8和UNC-73如何相互作用。WNTs是一种保守的糖蛋白，控制着线虫和哺乳动物生长锥体沿A/P轴的迁移。在线虫中，WNTS也沿着这个轴调节神经元的极性。我们的结果表明，VAB-8可以通过MIG-1 Frizzled型受体来调节Wnt信号，MIG-1和第二Frizzled型受体LIN-17拮抗MIG-1和第二Frizzled型受体LIN-17来控制PLM机械感觉神经元的极性。我们提出的实验将定义这些分子如何共同作用来调节神经元的极性，并筛选额外的分子来定义参与轴突引导和神经元极性的Wnt信号通路中的其他分子。3)确定ABL-1、CRML-1和UNC-53是否抑制VAB-8L和UNC-73的功能。我们的遗传学实验表明，这些保守的信号分子通过抑制VAB-8和UNC-73信号来调节轴突引导。我们建议检验这一假设，并定义他们用来调节VAB-8和UNC-73的机制。

DESCRIPTION (provided by applicant): Neuronal cell body and growth cone migrations shape the overall pattern and connectivity of nervous systems. The objective of the proposed research is to investigate the mechanisms that control neuronal migrations. Understanding these basic mechanisms could lead to insights into how damaged nervous systems might be repaired. The proposal has three specific aims. 1) To determine how VAB-8 and the Trio homolog UNC-73 regulate guidance receptors. A large variety of axon trajectories are guided by a few conserved guidance molecules. Many guidance receptors are broadly expressed posing the question of how neurons select among specific guidance cues to initiate and terminate directed growth. We have found that the kinesin-related molecule VAB-8 regulates the sensitivity to guidance cues by controling the levels of their receptors at the cell surface, VAB-8 acts though the conserved Rac GEF UNC-73/Trio. The focus of this aim is to show that the physical interactions between UNC-73, VAB-8 and the guidance receptors SAX-3/Robo, UNC-5 and UNC-40 mediate the effects of VAB-8 on these receptors, to show that the effects of VAB-8 are mediated by Rac signaling and to define the mechanism that promotes the accumulation of these receptors at.the cell surface. 2) To determine how Wnt signaling, VAB-8 and UNC-73 interact. Wnts are conserved glycoproteins that control the migrations of growth cones along the A/P axis of C. elegans and mammals. In C. elegans Wnts also regulate neuronal polarity alng this axis. Our results indicate that VAB-8 can regulate Wnt signaling through the MIG-1 Frizzled receptors and that MIG-1 and the second Frizzled receptor LIN-17 antagonize one to control the polarity of the PLM mechanosensory neuron. We propose experiments that will define how these molecules act together to regulate neuronal polarity and screens to define additional molecules that act in the Wnt signaling pathways involved in axon guidance and neuronal polarity. 3) To determine whether ABL-1, CRML-1 and UNC-53 inhibit the function of VAB-8L and UNC-73. Our genetic experiments indicate that these conserved signaling molecules regulate axon guidance by inhibiting VAB-8 and UNC-73 signaling. We propose to test this hypothesis and define the mechanisms that they employ to regulate VAB-8 and UNC-73.