Intracellular signaling by DSCAM during retinal development

视网膜发育过程中 DSCAM 的细胞内信号传导

基本信息

批准号：
8332418
负责人：
Andrew Garrett
金额：
$ 3.52万
依托单位：
JACKSON LABORATORY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-25 至 2013-03-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8332418
关键词：
Adhesions Adhesives Amacrine Cells Aplysia Axon Binding Biological Neural Networks Cell Adhesion Molecule Gene Cell physiology Cells Chromosomes, Human, Pair 21 Data Defect Dendrites Development Dominant-Negative Mutation Down Syndrome Down Syndrome Cell Adhesion Molecule Drosophila genus Epitopes Event Fascicle Functional disorder Gene Expression Goals Homologous Gene Human Image In Vitro Knock-in Mouse Lead Masks Mediating Microscopy Modeling Molecular Mus Muscle fasciculation Mutant Strains Mice Mutation Nervous system structure Neurodevelopmental Disorder Neurons Orthologous Gene Pathology Phenotype Phosphotransferases Photoreceptors Prevention Process Protein-Serine-Threonine Kinases Proteins Retina Retinal Retinal Diseases Retinal Ganglion Cells Role Signal Transduction Structure Synapses System Tertiary Protein Structure Testing Time Tissues Trisomy Work design developmental neurobiology family structure horizontal cell human disease in vivo information processing insight member membrane-associated guanylate kinase mutant neural circuit neurodevelopment neuronal cell body novel strategies p21 activated kinase p21-activated kinase 1 research study scaffold synaptogenesis time use tool

项目摘要

DESCRIPTION (provided by applicant): In order for the nervous system to develop and function normally, many processes must occur. Neurons must be spaced appropriately, they must send out axons and dendrites that extend through the tissue to develop arbors and find targets, and they must form synapses to communicate with partners. Defects at any of these points can lead to dysfunction and neurodevelopmental disorders. The Down syndrome cell adhesion molecule (Dscam) gene is on the region of chromosome 21 that is associated with trisomies in Down syndrome. In the mouse retina, Dscam and the very similar Dscam Like (DscamL1) are involved in adhesive masking, a cellular process important for self-avoidance, allowing cell spacing and dendrite arborization. The Dscams are also involved in some aspects of synapse development. There are a few proteins known to interact with the Dscams: Pak1 (p21-activated kinase) can be activated by Dscam, and the MAGI (membrane- associated guanylate kinase with inverted domain structure) family of scaffolding molecules interacts with the c-terminus of the Dscams. The aim of the experiments described in this proposal is to elucidate the signaling mechanisms downstream of the Dscams during adhesive masking and synapse development. The overall hypothesis is that Dscams regulate adhesive masking early in development through activation of Pak1, and are important for synapse maturation later in development through interactions with the MAGI proteins. To test this hypothesis, retina ganglion cells will be cultured in a system that allows the assessment of adhesive masking and the manipulation of gene expression. Experiments will also be performed in the mouse by making new mouse lines in which Dscam and DscamL1 have targeted mutations that do not allow the proteins to interact with the MAGIs. It is expected that the results will show that the Dscams carry out their different functions through distinct signaling mechanisms. These findings will have implications for the mechanisms of the Dscams' possible role in the pathology of Down syndrome and other neurodevelopmental disorders including congenital retinopathies.

描述（由申请人提供）：为了使神经系统正常发展和功能，必须发生许多过程。神经元必须适当间隔，它们必须发送轴突和树突，这些轴突和树突延伸到组织以发展arbors并找到靶标，并且必须形成突触才能与伴侣交流。这些点的缺陷都会导致功能障碍和神经发育障碍。唐氏综合征细胞粘附分子（DSCAM）基因位于与唐氏综合征中三角体相关的21染色体区域。在小鼠视网膜中，DSCAM和非常相似的DSCAM（DSCAML1）参与了粘合剂遮罩，这是一种对自我避免的细胞过程，允许细胞间距和树突含量。 DSCAM还参与了突触发展的某些方面。有几种已知与DSCAM相互作用的蛋白质：PAK1（P21激活激酶）可以通过DSCAM激活，而MAGI（膜 - 悬岩与倒置结构域结构的膜相关的鸟烷化激酶）家族的家族均与DSCAMS的C-terminus相互作用。本提案中描述的实验的目的是阐明在粘合性掩盖和突触发育过程中DSCAM下游的信号传导机制。总体假设是，DSCAMS通过激活PAK1在发育早期调节粘合剂遮罩，对于以后通过与Magi蛋白相互作用而发育的突触成熟很重要。为了检验该假设，将在允许评估粘合剂掩盖和操纵基因表达的系统中培养视网膜神经节细胞。实验还将通过制造新的小鼠系在小鼠中进行，其中DSCAM和DSCAML1具有不允许蛋白质与MAGIS相互作用的靶向突变。预计结果将表明DSCAM通过不同的信号传导机制执行其不同的功能。这些发现将对DSCAM在唐氏综合症和其他神经发育疾病（包括先天性视网膜病）的病理学中的可能作用有影响。