REGULATION OF NEURAL CAMS BY GROWTH FACTORS AND ACTIVITY

描述(改编自申请人的摘要)：一些神经摄像头有 已被确认，并在申请人的实验室和其他人的工作 证明了这些分子在分子的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，给定的时间和地点 CaM在发育过程中的表达是其功能的关键。这个 申请者最近的研究主要集中在确定转录 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标 配对结构域(Pax)蛋白，调节整个神经模式。他 建议通过检查骨骼生长因子是如何 形态发生蛋白(BMP)家族和突触活性调节 N-CAM和L1基因的表达。申请的具体目标是： 1)检测BMP2和BMP4对N-CAM和L1基因表达的调节 在神经细胞中；2)在转基因小鼠中确定 N-CAM和L1基因中的同源结构域和配对结构域结合元件 它们的发育表达模式和BMP反应；3)鉴定 参与诱导的调控元件和转录因子家族 通过神经活动对L1和N-CAM基因进行编码。转基因细胞和海马区 来自正常和转基因小鼠的切片培养将与 在这些实验中进行了凝胶位移和超位移分析。总体而言，这些研究 将阐明BMP信号以及特定的同源结构域和Pax的作用 基因产物对两种神经钙调蛋白表达的调节。会的 还提供了第一批演示之间的联系之一 CaM的转录调控和突触活性。这些结果将是 鉴于CAM在大脑中的中心作用，这一点尤其重要 发育、神经疾病和突触可塑性。

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.