REGULATION OF NEURAL CAMS BY GROWTH FACTORS AND ACTIVITY

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DESCRIPTION (Adapted from applicant's abstract): A number of neural CAMs have been identified, and work in the applicant's laboratory and others has demonstrated the importance of these molecules in the formation and function of the nervous system. It is clear from these studies that when and where a given CAM is expressed during development are critical for its function. The applicant's recent studies have focused on determining the transcription factors that regulate the expression of N-CAM and another neural CAM, L1. He has shown that the genes for these molecules are targets of the homeodomain and paired domain (Pax) proteins that regulate overall neural patterning. He proposes to expand these studies by examining how growth factors of the bone morphogenetic protein (BMP) family and synaptic activity modulate the expression of the N-CAM and L1 genes. The specific aims of the application are: 1) To examine the regulation of N-CAM and L1 gene expression by BMP2 and BMP4 in neural cells; 2) To determine in transgenic mice the contributions of the homeodomain and paired domain binding elements in the N-CAM and L1 genes to their developmental expression patterns and BMP responses; 3) To identify the regulatory elements and transcription factor families involved in the induction of the L1 and N-CAM genes by neural activity. Transfected cells and hippocampal slice cultures from normal and transgenic mice will be used in conjunction with gel shift and supershift assays in these experiments. Overall, these studies will elucidate the role of BMP signaling and of specific homeodomain and Pax gene products in the regulation of the expression of two neural CAMs. It will also provide one of the first demonstrations of the links between transcriptional regulation of CAMs and synaptic activity. These results will be particularly significant in view of the central role of CAMs in brain development, neurological disease and synaptic plasticity.