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. ? ?
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