The establishment of the functional nervous system depends upon the guidance of axons to their correct targets during embryonic development. The interactions of semaphorins and neuropilins have been strongly implicated in directing developing axons in this process. However, the specificity of neuropilins actions and the functions of neuropilin-2 in axon guidance in vivo are unknown. Intensive studies have strongly suggested the presence of additional component(s) or co-receptors in the neuropilin receptor complex. However, the molecular identity of the putative co- receptor remains mysterious. We have generated neuropilin-2 knockout mice. I propose to analyze the phenotype, especially the axon guidance defects, of the knockout mice to further understand the in vivo function of neuropilin-2. In addition, I propose to employ two different strategies to isolate and identify the putative Co-receptor(s) involved in semaphorin/neuropilin interactions. These approaches will greatly advance our knowledge of the mechanisms through which chemorepulsive cues and their receptors exert their effects directing axons to their proper targets.