Defects in neuronal migration and axonal guidance underlie many inherited and sporadic human disorders, yet the molecular mechanisms that control the final position of neurons and their wiring remain elusive. Both neuronal migration and axonal guidance is controlled by secreted or substrate-bound molecules that act as attractants or repellents. Several guidance cues, including the secreted netrins, have been shown to be bifunctional; that is they have both attractive and repulsive properties. The investigators have cloned the rostral cerebellar malformation (rcm) gene and shown that it encodes a member of a gene family with homology to UNC-5, a C. elegans transmembrane receptor necessary for dorsal circumferential cell and axon migrations away from netrin sources. Hence this mutation has been renamed Unc5h3rcm. They have demonstrated that this netrin receptor is necessary for the exclusion of migrating cerebellar granule cells from the midbrain and brainstem in the developing embryo, suggesting that neurons normally respond to repulsive cues expressed in the neighboring midbrain and brainstem during fonnation of the cerebellum. It is clear that UNC5H3 is necessary for guidance of migrating neurons, however the role of the vertebrate UNC-5 receptors in axonal pathfinding is unknown. Similarly, the signaling mechanisms utilized by the UNC-5 receptors which lack catalytic domains, remain to be elucidated. This application proposes to investigate the role of UNC5H3 in axonal guidance in vivo, and to examine the interactions of proteins that bind to the cytoplasmic signaling domain of UNC5H3. The high expression of other netrin receptors in the developing cerebellum suggests that these proteins, in addition to UNC5H3, might play an important role in the formation of this structure. They have isolated a new hypomorphic allele of another netrin receptor, Deleted in colorectal cancer (DCC), a member of the UNC-40 family. This new Dcc mutation, along with the targeted null allele, allows for examination of the effects of a graded reduction in DCC on CNS development, particularly in the developing cerebellum. Lastly, because genetic evidence suggests that UNC-40 may have a modulatory or compensatory role in the control of UNC-5-mediated migrations in C. elegans, they will examine mice with mutations in both Unc5h3 and Dcc for compensatory roles of UNC5H3 and DCC in CNS development.
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