The basic principle underlying this work is that identification of strongly developmentally regulated and cell specific genes expressed in the cerebellum provides an opportunity to investigate detailed molecular mechanisms controlling formation of the mammalian CNS. These genes provide the tools both for discovery of transduction pathways critical in the specification and differentiation of cerebellar cell types, and for the exploration of novel biochemical pathways in which their products function. The identification of these mechanisms is critical for understanding both human health and disease. Thus, studies of the transcription factor RU49 and its associated partners will provide insights into cerebellar granule cell growth and differentiation that are directly relevant to medulloblastoma, the most common form of childhood brain tumor. Analysis of brain lipid binding protein (BLBP) and its ligand docosahexanoic acid (DHA) will provide a biochemical basis for understand- ing the utilization of this essential nutrient, which has recently been demonstrated to be required for timely development of the human CNS. And identification of additional molecules involved in critical stages of CNS development will provide tools for investigating other pathways affected in a variety of congenital disorders. To accomplish these goals will require: 1) further characterization of cDNA clones that identify genes involved in development of the cerebellum; 2) identification of the specific functions of RU49 and its associated partners in growth and differentiation of CNS granule cells; 3) investigation of mechanisms regulating RU49 expression using the biolistic transfection procedures developed during the prior period of this project; 4) investigation of the role of brain lipid binding protein (BLBP) and its high affinity ligand docosahexanoic acid (DHA) in CNS development and determine whether DHS is a critical signal for radial glial cell differentiation; 5) identification of the transcription factors controlling expression of BLBP in glial cells in response to neurons and test the idea that these factors include a putative DHA nuclear receptor.
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