Developmental defects in neuronal migration, maturation and connectivity are commonly found in human neurological diseases including epilepsy, schizophrenia and mental retardation. The acquisition of appropriate neuronal features during brain development is crucial for its function in adult life. However, the molecular mechanisms that regulate many aspects of brain development are poorly understood. The best characterized factor that determines the cytoarchitecture of cortical brain structures is reelin, the gene disrupted in the mutant reeler mouse, in the absence of the Reelin protein, many aspects of brain development are abnormal including neuronal migration, leading to the disruption of cellular layers, and dendrite development. Reelin is an extracellular protein produced in cortical marginal layers and subject to proteotytic cleavage. It was previously demonstrated that the Reelin signal that controls cortical layer formation is mediated by two cell surface receptors, the very low-density lipoprotein receptor (VLDLR) and apolipoprotein E receptor 2 (ApoER2), and by the intracellular adapter protein Disabled1 (Dab1). In addition, Reelin possesses a protease activity that could also be important for brain development. In superficial Reelin-rich layers, most principal neurons terminate their migration and develop an initial dendritic arborization. However, it is unclear whether Reelin directly regulates dendrite growth and little is known about the cellular events that mediate its function. We propose that Reelin functions by inducing cytoskeletal changes that enable correct neuronal positioning during embryonic development and dendrite maturation in the postnatal brain. In this proposal, we will test the hypothesis that Reelin directly regulates the growth of hippocampal pyramidal cell dendrites and elucidate the molecular events that mediate this function. A combination of biochemical, genetic, cell biology and molecular approaches will be taken to test our hypothesis. Recombinant Reelin will be purified and characterized biochemically, hippocampal dendrite development will be studied in vivo and in vitro using mutant and transgenic mice, and novel downstream targets of Reelin will be identified by genetic screens. Our studies will lead to a better understanding of Reelin function in normal brain development. Furthermore, our findings may have significant implications for cognitive disorders associated with Reelin deficiency.
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