CELL ADHESION MOLECULES IN NERVOUS SYSTEM DEVELOPMENT

描述(摘自申请者摘要)：神经细胞黏附分子 L1在发育中的某些类迁移神经元前体上发现 神经系统和几乎所有的中枢神经投射轴突 系统和外周神经系统。不足为奇的是，它被牵连到 轴突束的丛生和某些神经前体的迁移 在各种体外系统中。在20世纪90年代初，S被证明在 人类的L1基因会导致严重的精神发育迟缓 发育不全、拇指内收、痉挛截瘫和脑积水)。我们有 分析了L1基因不同突变的个体，发现 导致L1表达丧失的突变比 仅改变L1细胞质区域的突变。然而，突变的基因 细胞质区域足以导致轴突引导失败 精神发育迟滞。最近，我们和其他人分析了L1基因敲除 老鼠，并发现它的表型与人类非常相似 X连锁脑积水。这包括脑积水，异常发育 皮质脊髓束与小脑虫和小脑体发育不全 老茧。在这个项目中，我们建议检验L1中介的假设 粘连对于小脑蠕虫的正常发育是必不可少的 L1胞质结构域的功能对细胞的发育至关重要 皮质脊髓束。为此，我们将使用特定的命令生成新的鼠标行 L1细胞质结构域的改变。我们还将分析老鼠中的 L1的第6个Ig结构域被移除，删除了L1中的RGD序列， 使我们能够评估L1同型结合和L1同型结合之间的差异 大脑发育过程中的L1-整合素相互作用。最后，我们将承诺 小鼠小脑发育的首次仔细分析 缺席L1。

DESCRIPTION (From the Applicant's Abstract): The neural cell adhesion molecule L1 is found on some classes of migrating neuronal precursors in the developing nervous system and on almost all projection axons in both the central nervous system and peripheral nervous system. Not surprisingly, it has been implicated in the fasciculation of axon bundles and in migration of some neural precursors in various in vitro systems. In the early 1990's it was shown that mutations in the L1 gene in humans cause severe mental retardation (corpus callosum hypoplasia, adducted thumbs, spastic paraplegia, and hydrocephalus). We have analyzed individuals with different mutations in the L1 gene and discovered that mutations that lead to a loss of L1 expression are much more severe than mutations that only alter the cytoplasmic domain of L1. However, mutations of the cytoplasmic domain are sufficient to cause axon guidance failures and mental retardation. Recently, we and others have analyzed the L1 knock-out mouse and discovered that it has a phenotype remarkably similar to humans with X-linked hydrocephalus. This includes hydrocephalus, abnormal development of the corticospinal tract, and hypoplasia of the cerebellar vermis and corpus callosum. In this project we propose to test the hypothesis that L1 mediated adhesion is essential for normal development of the cerebellar vermis and that the function of the L1 cytoplasmic domain is essential for development of the corticospinal tract. To do this we will generate new mouse lines with specific alterations in the L1 cytoplasmic domain. We will also analyze mice in which the 6th Ig domain of L1 has been removed, deleting the RGD sequence in L1, allowing us to evaluate the difference between L1 homophilic binding and L1-integrin interactions during brain development. Finally, we will undertake the first careful analysis of cerebellar development in mice with altered or absent L1.