Genetic Dissection of L1-type Neural Cell Adhesion Molecules in a Developing Nervous System

摘要：细胞粘附分子L1家族的细胞表面蛋白主要参与许多发育过程，特别是在神经系统的形成期间。 它们与外部大量不同的蛋白质相互作用，以及表达这些分子的细胞内部。 虽然L1蛋白的一些功能特性在从线虫到人类的广泛物种中很好地保守，但最近在进化过程中开发了其他功能和结合伴侣。 拟议的研究试图通过分析L1型蛋白在特定发育过程中的结构和功能要求来剖析L1蛋白的这种功能复杂性。 该研究计划将集中在果蝇神经系统的形成。 不表达任何L1型蛋白质的突变果蝇胚胎死亡，并在发育中的神经系统和许多其他组织中表现出许多微妙的异常。 在L1型基因突变的果蝇胚胎中，一些神经没有适当地形成，特定的神经元细胞无法与其靶细胞建立正确的细胞连接。 天然的，以及人工改变和突变的L1型蛋白将被重新引入到这些胚胎中，以测试它们是否能够拯救由于缺乏内源性果蝇L1蛋白而引起的特定神经畸形。 这种分析将揭示L1型蛋白的分子功能和相互作用在哪种类型的细胞中需要支持某些发育过程。

Abstract: Cell surface proteins of the L1 family of cell adhesion molecules are centrally involved in numerous developmental processes, especially during the formation of the nervous system. They interact with a large number of different proteins on the outside, as well the inside of cells that express such molecules. Whereas some functional properties of L1 proteins are well conserved in a wide range of species, from nematodes to humans, other functions and binding partners have been developed more recently during evolution. The proposed research tries to dissect this functional complexity of L1 proteins by analyzing the structural and functional requirements for L1-type proteins in specific developmental processes. The research plan will focus on the formation of the nervous system in the fruitfly Drosophila melanogaster. Mutant Drosophila embryos that do not express any L1-type proteins die and exhibit many subtle abnormalities in their developing nervous system and a number of other tissues. In Drosophila embryos with mutations in their L1-type gene, several nerves are not appropriately formed and specific neuronal cells are unable to make the correct cellular connections with their targets. Natural, as well as artificially altered and mutant L1-type proteins will be reintroduced into such embryos to test whether they are able to rescue specific neurological malformations that are caused by the absence of the endogenous Drosophila L1 protein. This analysis will shed light on what molecular functions and interactions of L1-type proteins are required in which types of cells to support certain developmental processes.