Cell Adhesion Molecules in CNS Development

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DESCRIPTION (provided by applicant): Developmental defects and degenerative changes that affect the central nervous system (CNS) lead to neurological disorders including dementia, epilepsy, schizophrenia, Parkinson's and Alzheimer's disease. An understanding of the mechanisms that regulate CNS development and function is expected to provide insights into the molecular pathogenesis of neurological disorders. The development and physiology of neurons is regulated by their interactions with neighboring cells and with extracellular matrix (ECM) molecules. The mechanisms by which receptors that mediate these interactions regulate neuronal development and health are poorly defined. Our long-term goal is to understand the mechanisms by which cell-cell and celI-ECM interactions regulate CNS development, maintenance, and function. We propose here to study ECM receptors of the beta1-integrin family in the CNS. We hypothesis that beta1-integrins are part of a regulatory network that controls cell cycle progression of cortical precursor cells in the CNS. To test our hypothesis, we will use genetically modified mice carrying floxed alleles, Cre, and GFP to analyze by BrdU labeling and immunohistochemistry defects in cell proliferation and differentiation of beta1 integrin-deficient CNS precursors in vivo, and after FACS sorting in vitro. Our preliminary data validate our hypothesis. They show that beta1-integrins regulate proliferation in neurogenic zones of the CNS. We expect that beta1 -integrins are part of the regulatory circuit that coordinates cell-cycle exit with differentiation and migration. The identification of the mechanisms that regulate these events is important to understand CNS development and disease progression, as well as to control the behavior of neural stem cells in order to use them as therapeutic agents.