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）： 为了使神经系统发育和正常运作，必须发生许多过程。神经元必须间隔适当，它们必须发出轴突和树突，延伸穿过组织以形成乔木并找到目标，并且它们必须形成突触以与伙伴进行交流。其中任何一点的缺陷都可能导致功能障碍和神经发育障碍。唐氏综合症细胞粘附分子 (Dscam) 基因位于 21 号染色体区域，与唐氏综合症三体性相关。在小鼠视网膜中，Dscam 和非常相似的 Dscam Like (DscamL1) 参与粘附掩蔽，这是一种对于自我回避很重要的细胞过程，允许细胞间隔和树突分枝。 Dscam 还参与突触发育的某些方面。已知有一些蛋白质与 Dscam 相互作用：Pak1（p21 激活激酶）可被 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 Dscam 的 C 末端相互作用骗局。本提案中描述的实验的目的是阐明粘着掩蔽和突触发育过程中 Dscam 下游的信号传导机制。总体假设是，Dscams 通过激活 Pak1 在发育早期调节粘附掩蔽，并且通过与 MAGI 蛋白的相互作用对发育后期的突触成熟很重要。为了检验这一假设，视网膜神经节细胞将在一个系统中培养，该系统可以评估粘附掩蔽和操纵基因表达。还将在小鼠中进行实验，通过制作新的小鼠品系，其中 Dscam 和 DscamL1 具有不允许蛋白质与 MAGI 相互作用的靶向突变。预计结果将表明 Dscam 通过不同的信号机制发挥不同的功能。这些发现将对 Dscams 在唐氏综合症和其他神经发育障碍（包括先天性视网膜病）的病理学中可能发挥的作用机制产生影响。 公共卫生相关性： 本提案的目的是研究唐氏综合症细胞粘附分子 (Dscam) 的小鼠直系同源物和类似的 Dscam Like (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 位于与唐氏综合症三体性相关的 21 号染色体区域，了解 Dscam 功能的基本分子机制将有助于确定其在与唐氏综合症和其他神经发育障碍相关的表型中可能发挥的作用。研究视网膜中的这些机制也可以深入了解人类先天性视网膜病。