REGULATION OF NEURAL CAMS BY GROWTH FACTORS AND ACTIVITY

描述（改编自申请人的摘要）：许多神经CAM具有 已经确定，并且在申请人的实验室和其他人的工作已经 证明了这些分子在形成和功能中的重要性， 神经系统从这些研究中可以清楚地看出， CAM在发育过程中的表达对其功能至关重要。的 申请人最近的研究集中于确定转录 调节N-CAM和另一种神经CAM L1表达的因子。他 已经表明这些分子的基因是同源结构域的靶点， 配对结构域（Pax）蛋白，调节整体神经模式。他 建议通过研究骨骼的生长因子如何 形态发生蛋白（BMP）家族和突触活动调节 N-CAM和L1基因的表达。申请的具体目的是： 1)研究BMP 2和BMP 4对N-CAM和L1基因表达的调节作用 2）在转基因小鼠中，确定神经细胞中的 N-CAM和L1基因中的同源域和配对域结合元件， 它们的发育表达模式和BMP反应; 3）为了鉴定 参与诱导的调控元件和转录因子家族 L1和N-CAM基因的神经活动。转染细胞与海马 来自正常和转基因小鼠的切片培养物将与 在这些实验中的凝胶位移和超位移测定。总的来说，这些研究 将阐明BMP信号传导和特定同源结构域和Pax的作用， 基因产物在两种神经细胞粘附分子表达调控中的作用。它将 也提供了一个第一个演示之间的联系， CAM的转录调节和突触活性。这些结果将 鉴于CAM在大脑中的中心作用， 发育、神经系统疾病和突触可塑性。

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.