Neuronal migration in C. elegans

描述（由申请人提供）：神经元细胞体和生长锥迁移塑造了神经系统的整体模式和连接性。这项研究的目的是研究控制神经元迁移的机制。了解这些基本机制可以帮助我们了解受损的神经系统是如何修复的。该提案有三个具体目标。1)为了确定VAB-8和Trio同源物γ-73如何调节导向受体。大量的轴突轨迹是由一些保守的引导分子引导的。许多指导受体广泛表达，提出了神经元如何在特定的指导线索中选择启动和终止定向生长的问题。我们已经发现驱动蛋白相关分子VAB-8通过控制细胞表面受体的水平来调节对导向信号的敏感性，VAB-8通过保守的Rac GEF β-73/Trio起作用。该目的的重点是显示VAB-73、VAB-8和导向受体SAX-3/Robo、VAB-5和VAB-40之间的物理相互作用介导VAB-8对这些受体的作用，以显示VAB-8的作用由Rac信号传导介导，并确定促进这些受体在细胞表面积累的机制。2)为了确定Wnt信号传导，VAB-8和BAB-73如何相互作用。Wnt是一种保守的糖蛋白，控制着生长锥沿着C.和哺乳动物。In C.线虫Wnt还沿该轴调节神经元极性。我们的研究结果表明，VAB-8可以调节Wnt信号，通过β-1卷曲受体和β-1和第二卷曲受体LIN-17拮抗一个控制极性的PLM机械感觉神经元。我们提出的实验，将定义这些分子如何共同作用，以调节神经元的极性和屏幕，以确定其他分子的作用，在Wnt信号通路参与轴突的指导和神经元的极性。3)确定ABL-1、CRML-1和VAB-53是否抑制VAB-8L和VAB-73的功能。我们的遗传实验表明，这些保守的信号分子通过抑制VAB-8和VAB-73信号传导来调节轴突导向。我们建议测试这一假设，并确定他们用来调节VAB-8和VAB-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.