reproduced verbatim): Neuronal migration, the process by which neurons move from the germinal layers of the brain to their final destination in the cortex, is a critical step in the formation of the brain. Failure in this migration has been implicated in several disease states including epilepsy, mental retardation and schizophrenia. The long-term goal of this research is to understand the molecular and cellular mechanisms that induce and regulate neuronal migration. Neurons migrate in close association with glial cells, either radial glia or glial tubes, which provide a scaffold for neuronal movement. This application aims to further characterize the nature of the signals that induce 1) the formation of the glia scaffolds and 2) the migration of neurons along these glia. We have identified two molecules that mediate critical interactions between migrating neurons and their associated glia. We have shown that the growth factor neuregulin (NRG) is produced by neurons and activates erbB4 receptors in glia, leading to the formation of radial glia, which then in turn support the migration of neurons. We have recently found that glial cells secrete a soluble protein, which we have called MIA (Migration Inducing Activity) that induces the migration of neurons. Thus, NRG and MIA appear to be critical in the neuronglia interactions responsible for neuronal migration. The present application extends these observations to investigate the signaling mechanism by which these molecules induce neuronal migration.
Specific Aim 1 will use mutagenesis and phospho-peptide mapping to study erbB4 receptor signaling mechanisms, and test the hypothesis that the effects of this receptor tyrosine kinase are dependent upon specific features of erbB4.
Specific aim 2 will purify and clone the MIA protein, characterize its biological properties and test the hypothesis that the expression of MIA is regulated by NRG and erbB4 signaling.
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