Intracellular signaling by DSCAM during retinal development

视网膜发育过程中 DSCAM 的细胞内信号传导

• 批准号: 8198040
• 负责人: Andrew Garrett
• 金额: $ 5.13万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-25 至 2013-08-24
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8198040
• 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

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. PUBLIC HEALTH RELEVANCE: The aim of this proposal is to study the molecular mechanisms by which the mouse ortholog of Down syndrome cell adhesion molecule (Dscam) and the similar Dscam Like (DscamL1) function in the cellular recognition events that direct retinal development. In humans, Dscam is in region of Chromosome 21 associated with Down syndrome trisomies, and understanding the basic molecular mechanisms of the Dscams' function will help to define its possible role in the phenotypes associated with Down syndrome and other neurodevelopmental disorders. Studying these mechanisms in the retina may provide insight into human congenital retinopathies as well.

描述（由申请人提供）： 为了使神经系统正常发育和功能，必须发生许多过程。神经元之间必须有适当的间隔，它们必须发出轴突和树突，这些轴突和树突延伸穿过组织，形成树状结构，找到目标，它们必须形成突触，与伙伴进行交流。这些点的任何缺陷都可能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21号染色体上，与唐氏综合征的三体相关。在小鼠视网膜中，Dscam和非常相似的Dscam样（DscamL1）参与粘附掩蔽，这是一种对自我回避很重要的细胞过程，允许细胞间隔和树突树枝化。Dscams也参与突触发育的某些方面。已知有几种蛋白质与Dscams相互作用：Pak1（p21激活的激酶）可以被Dscam激活，支架分子的MAGI（具有反向结构域结构的膜相关鸟苷酸激酶）家族与Dscams的c-末端相互作用。在这个建议中描述的实验的目的是阐明下游的Dscams在粘合剂掩蔽和突触发育过程中的信号传导机制。总体假设是Dscams通过激活Pak1在发育早期调节粘附掩蔽，并且通过与MAGI蛋白的相互作用在发育后期对突触成熟很重要。为了验证这一假设，将在允许评估粘附掩蔽和操纵基因表达的系统中培养视网膜神经节细胞。实验也将在小鼠中进行，通过制作新的小鼠品系，其中Dscam和DscamL1具有靶向突变，不允许蛋白质与MAGI相互作用。预计结果将表明，Dscams通过不同的信号机制执行其不同的功能。这些发现将对Dscams在唐氏综合征和其他神经发育障碍（包括先天性视网膜病变）的病理学中可能发挥作用的机制产生影响。 公共卫生关系： 本研究的目的是研究唐氏综合征细胞粘附分子（Dscam）和类似Dscam样分子（DscamL1）在指导视网膜发育的细胞识别事件中发挥作用的分子机制。在人类中，Dscam位于与唐氏综合征三体相关的21号染色体区域，了解Dscams功能的基本分子机制将有助于确定其在与唐氏综合征和其他神经发育障碍相关的表型中的可能作用。研究视网膜中的这些机制也可以提供对人类先天性视网膜病的深入了解。