Disorders in the placement of neurons during development can be devastating to the function of the nervous system. Relatively mild neuronal ectopias can lead to epilepsy while widespread neuronal dysplasias lead to severe mental retardation. This project studies the molecular machinery that regulates the migration and positioning of neurons during embryonic brain development. In particular, we are focused on a molecular cascade that involves at least 4 known gene products that relay a signal that regulates the cellular properties of migrating neurons and direct them to the appropriate layers. These proteins include a extracellular protein Reelin, that is produced in discrete regions of the developing brain, ApoER2 and VLDL2 two membrane spanning receptors and Dab1 a cytoplasmic signaling molecule. The binding of Reelin to the receptors induces the tyrosine phosphorylation of Dab1. We have found tyrosine phosphorylation of Dab1 fosters interactions between Dab1 and SH2 domain molecules such as Nckbeta and Crk. These molecules have previously been shown to interact with molecules that regulate cytoskeletal dynamics. We are currently establishing models to determine the role of these molecules in neuronal placement. Another interest in the lab is the role of these molecules in the maintenance of the adult nervous system. To study this we have developed a mouse line that harbors a conditional allele for Dab1, that can be inactivated by the regulated expression of the Cre recombinase. The goal of this work is to inactivate Dab1 in the nervous system after it has formed correctly, and determine if this causes any nervous system dysfunction.
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