This program brings together different scientific disciplines to elucidate biochemical, biological and genetic aspects of processes that relate to mental retardation and developmental disabilities. The goals of the proposed program are to investigate the mechanisms that control cell-cell interactions, cell migration and differentiation during development of the nervous system. A disarray in these interactions results in aberrations of neural development as seen in the 'migrational disorders' that cause severe mental retardation and profound disability in humans. A primary step in understanding these developmental processes is the characterization of regulatory molecules that are involved. The program consists of five closely integrated projects and two supporting cores. Collectively, they address the central postulate that specific glycoconjugate molecules, which are expressed at discrete stages during development, influence neural cell interactions through their receptors (lectins) and promote subsequent cellular responses. The processes are also regulated and modified by transcription factors, differential splicing, cytokines and growth factors. Overall they define neuronal cell morphology and architecture through cytoskeletal elements. All projects in this application address the molecular mechanisms involved in the cell migration and morphogenesis of brain. Understanding these processes is directly relevant to migrational disorders. Project by Dr. Jungalwala will focus on the role of sulfoglucuronyl carbohydrate and its endogenous lectins in cellular interactions during the migration of granule cell neurons. Project by Dr. McCluer will examine the chemical nature and function of stage specific embryonic antigen 1 (SSEA-1) carbohydrate in cerebellar development. Project by Dr. McCaffery will study the expression and regulation of retinoic acid produced in the choroid plexus, and its effect on proliferation and neurite outgrowth of cerebellar neurons. Project by Dr. Andreadis will examine the role of alternative splicing mechanisms and other factors that regulate tau protein gene expression and function during development. Project by Dr. Jungalwala will provide instrumental and administrative support to the program. Dr. Andreadis will provide molecular biology support necessary for all projects in the application. The interdisciplinary, interactive and focused approach to the role of specific molecules involved in cellular interactions, migration and differentiation should enrich our understanding of fundamental mechanisms of brain development. The findings are essential for understanding abnormal brain development and a broad spectra of migrational disorders. This knowledge will be beneficial for the eventual prevention and treatment of developmental disorders.
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