Neuronal migration defects have been described in many human neurological disorders, including neurodevelopmental abnormalities, pediatric epilepsy and schizophrenia. Furthermore, one of the major problems encountered in the treatment of brain tumors is the ability of cancer cells to disseminate throughout the central nervous system. The study of ataxic mutations in mice has led to the identification of several genes that function in the control of cell positioning during brain development. In particular, starting with the identification of the Reelin gene in 1995, several components of a signaling pathway have been uncovered that are critical for the formation of laminar structures. This competitive renewal is based on our initial discovery of Reelin and the advances made in the previous funding period that elaborated the Reelin signaling pathway. Reelin is a large secreted protein that binds to lipoprotein receptors and induces tyrosine phosphorylation and degradation of Disabled-1 (Dab-1). This signal relay is required for splitting of the preplate and formation of the cortical plate, migration of Purkinje cells and several other cell positioning events in the brain and spinal cord. We propose a multidisciplinary approach to elucidation of the molecular and biological events controlled by the Reelin pathway. A combination of molecular biology, protein biochemistry, cell biology and whole animal studies have been designed in three synergistic specific aims.
The first aim concerns the purification and characterization of Reelin with an emphasis on its interaction with lipoprotein receptors and other cell surface or extracellular proteins. Intracellular signaling events leading to phosphorylation of Dab-1 and the subsequent function of Dab-1 will be pursued, taking advantage of the protein interactions uncovered in the previous funding period. Finally, transgenic mice, brain slice cultures and dissociated cultures will be used to study the functional roles of components of the Reelin signaling pathway in neurons. This proposal will generate new information concerning the mechanisms responsible for brain development and nerve cell function. These studies will have important implications for several pathological conditions, including pediatric epilepsy, schizophrenia and Alzheimer's disease.
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