DESCRIPTION (provided by applicant): The nervous system is made of a large number of neurons, precisely connected by axons. This complex axonal network is important to all behavioral functions and is established largely during embryogenesis under the control of a variety of guidance molecules. Abnormal development may lead to errors in neuronal connections, causing various neurological and mental disorders. The long-term objective is to understand the growth cone signaling mechanisms controlling directional growth of axons in building neural circuits. Understanding molecular mechanisms underlying axon pathfinding may provide crucial tools for axonal regeneration in the adult central nervous system following injury. A merging theme in axon guidance is that multiple signaling pathways are frequently found to function in one single neuron, raising a fundamental question of how the signaling pathways are integrated in the same growth cone, the cellular apparatus located at the tip of the axon responsible for sensing guidance cues and growth cone steering. Two major chemorepellent pathways, the Semaphorin/Neuropilin pathway and the Slit/Robo pathway, were discovered separately. Preliminary studies suggest an unexpected crosstalk between the two signaling pathways. The goal of the proposed research is to explore the mechanism of the crosstalk between these two major chemorepellent pathways and the biological significance of growth cone signaling convergence. The proposed study will shed light on the organization of axon guidance signaling pathways and further the understanding of molecular mechanisms of nervous system development .