Role of molecular recognition in retinal patterning and synaptic organization

分子识别在视网膜图案化和突触组织中的作用

• 批准号: 8128501
• 负责人: PETER Gerard FUERST
• 金额: $ 23.28万
• 依托单位: UNIVERSITY OF IDAHO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8128501
• 关键词: Adhesions; Alleles; Alternative Splicing; Amacrine Cells; Biological Assay; Biomedical Research; Birth; Cell Adhesion Molecules; Cell Count; Cell Death; Cells; Cellular Stress; Chromosomes, Human, Pair 21; Code; Communities; Complex; Coupled; Cues; Development; Developmental Process; Disease; Down Syndrome; Down Syndrome Cell Adhesion Molecule; Drosophila genus; Environment; Etiology; Eye; Funding; Genes; Goals; Homologous Gene; Incidence; Ligands; Light; Mediating; Modeling; Molecular; Mus; Mutant Strains Mice; Mutation; Nervous system structure; Neurites; Neurons; Neurosciences; Pathology; Patients; Pattern; Phenotype; Play; Process; Protein Isoforms; Publishing; RNA Splicing; Regulation; Reporting; Research; Research Proposals; Retina; Retinal; Retinal Ganglion Cells; Role; Scientific Advances and Accomplishments; Series; Staging; Stress; Synapses; System; Testing; Time; Trisomy; Universities; Vertebrates; Visual; Washington; Work; axon guidance; career; cell type; dosage; gene function; genetic resource; light deprivation; molecular recognition; monocular; mouse model; mutant mouse model; nervous system development; neural patterning; neurodevelopment; neuron loss; neuronal cell body; overexpression; prevent; programs; public health relevance; receptor; relating to nervous system; research study; retinal rods

DESCRIPTION (provided by applicant): Candidate and Environment: Dr. Peter Fuerst will conduct the research contained within this proposal at Washington State University. Washington State University is an ideal environment in which to conduct advanced biomedical research using mouse models and in which to advance a research program. Research Proposal: The research we propose will use mouse models to identify the molecular mechanisms underpinning development of the retina. The mouse models, all developed by the applicant, include a conditional allele of the Down syndrome cell adhesion molecule, Dscam, as well as an allelic series of mouse mutant Dscam strains and a null allele of the Dscam homologue Dscam-like1 (Dscaml1). Dscam and Dscam- Like1 are essential for normal development of the nervous system and Dscam is proposed to contribute to the pathology of Down syndrome. In the retina, Dscam is required for soma mosaic spacing, regulation of cell number and neurite arborization and lamination. Our published results concerning Dscam and Dscaml1 are the first demonstrations of mutations found to ablate mosaic patterning and the first genes shown to mediate isoneuronal and heteroneuronal repulsion in vertebrates. Specific Aims: We propose to use the Dscam and Dscaml1 mutant mouse models to discover mechanisms underpinning development of the retina and to probe the function of Dscam in the mammalian nervous system. This will be accomplished by testing the following hypotheses detailed in this research proposal. Hypotheses: 1) We will test the hypothesis that DSCAM mediates multiple distinct functions using an allelic series and conditional allele of Dscam mouse mutant lines to genetically and temporally isolate Dscam-dependent developmental processes. 2) We will test the hypothesis that DSCAM mediates adhesion between cell types and repulsion within cell types and that DSCAM activity in the retina is mediated by homophillic interactions and not by a ligand-receptor mechanism by using a conditional allele coupled to cell type specific deletion. 3) We will test the hypothesis that Dscam and Dscaml1 regulate normal developmental cell death. Long-term goals: This research will uncover fundamental aspects of neural organization and provide the funding necessary for Dr. Fuerst to establish a successful academic career focused on hypothesis driven biomedical research. Significance: Neurite arborization, regulation of cell number and soma mosaic spacing are fundamental aspects of neurodevelopment that are not currently well understood at the molecular level in vertebrates. Our preliminary research indicates that DSCAM plays a vital role in mediating these processes in the mammalian nervous system. Identifying mechanisms by which DSCAM functions using a series of mouse mutant alleles and a conditional allele will contribute to our understanding of nervous system development and the causation of disorders associated with neural dysgenesis and also contribute valuable research models to the neuroscience community. PUBLIC HEALTH RELEVANCE: The primary goal of the proposed work is to understand how molecular recognition cues facilitate neural patterning. Research will focus on discovering the mechanisms by which two recognition cues; the Down Syndrome Cell Adhesion Molecule (Dscam) and its homologue Dscam-like1 (Dscaml1), mediate circuit formation within the retina. Both Dscam and Dscaml1 are required for neurite lamination, neurite arborization and regulation of cell number. Therefore, understanding the mechanism by which these molecules function will advance scientific understanding of neural development on multiple fronts. Furthermore, decreasing Dscam dosage decreases the incidence of retinal developmental cell death suggesting that the retina may provide an excellent system in which to model enhanced developmental cell death of neurons that occurs in Down syndrome patients, who overexpress Dscam as a result of Chromosome 21 trisomy.

描述（由申请人提供）： 候选人和环境：Peter Fuerst 博士将在华盛顿州立大学开展本提案中包含的研究。华盛顿州立大学是使用小鼠模型进行先进生物医学研究和推进研究项目的理想环境。研究提案：我们提出的研究将使用小鼠模型来确定支撑视网膜发育的分子机制。所有小鼠模型均由申请人开发，包括唐氏综合症细胞粘附分子Dscam的条件等位基因，以及小鼠突变体Dscam品系的等位基因系列和Dscam同源物Dscam-like1 (Dscaml1)的无效等位基因。 Dscam 和 Dscam-Like1 对于神经系统的正常发育至关重要，并且 Dscam 被认为有助于唐氏综合症的病理学。在视网膜中，Dscam 是体细胞镶嵌间距、细胞数量调节以及神经突树枝化和层压所必需的。我们发表的有关 Dscam 和 Dscaml1 的结果首次证明了发现的突变可以消除镶嵌图案，并且是第一个被证明可以介导脊椎动物中异神经元和异神经元排斥的基因。具体目标：我们建议使用 Dscam 和 Dscaml1 突变小鼠模型来发现视网膜发育的机制，并探讨 Dscam 在哺​​乳动物神经系统中的功能。这将通过测试本研究提案中详细说明的以下假设来实现。假设：1）我们将使用 Dscam 小鼠突变系的等位基因系列和条件等位基因在遗传上和时间上分离 Dscam 依赖性发育过程来检验 DSCAM 介导多种不同功能的假设。 2）我们将测试 DSCAM 介导细胞类型之间的粘附和细胞类型内的排斥的假设，并且视网膜中的 DSCAM 活性是由同性相互作用介导的，而不是通过使用与细胞类型特异性缺失偶联的条件等位基因的配体-受体机制介导的。 3) 我们将检验 Dscam 和 Dscaml1 调节正常发育细胞死亡的假设。长期目标：这项研究将揭示神经组织的基本方面，并为 Fuerst 博士提供必要的资金，以建立专注于假设驱动的生物医学研究的成功学术生涯。 意义：神经突分枝、细胞数量调节和体细胞镶嵌间距是神经发育的基本方面，目前在脊椎动物的分子水平上尚未得到很好的理解。我们的初步研究表明 DSCAM 在调节哺乳动物神经系统的这些过程中发挥着至关重要的作用。使用一系列小鼠突变等位基因和条件等位基因识别 DSCAM 的功能机制将有助于我们了解神经系统发育和与神经发育不全相关的疾病的病因，并为神经科学界贡献有价值的研究模型。 公共健康相关性：拟议工作的主要目标是了解分子识别线索如何促进神经模式。研究重点是发现两种识别线索的机制；唐氏综合症细胞粘附分子 (Dscam) 及其同源物 Dscam-like1 (Dscaml1) 介导视网膜内的回路形成。 Dscam 和 Dscaml1 都是神经突层压、神经突分枝和细胞数量调节所必需的。因此，了解这些分子发挥作用的机制将在多个方面促进对神经发育的科学理解。此外，减少 Dscam 剂量可降低视网膜发育细胞死亡的发生率，这表明视网膜可能提供一个极好的系统来模拟唐氏综合症患者中发生的神经元发育性细胞死亡的增强，这些患者由于 21 号染色体三体性而过度表达 Dscam。