Role of molecular recognition in retinal patterning and synaptic organization

摘要：候选人和环境：Peter Fuerst博士将进行这项研究 华盛顿州立大学的提案。华盛顿州立大学是一个理想的学习环境 使用小鼠模型进行高级生物医学研究，并在其中推进研究计划。 研究建议：我们提出的研究将使用小鼠模型来确定分子机制 支撑着视网膜的发育。所有由申请者开发的鼠标模型包括一个 唐氏综合征细胞黏附分子Dscam的条件等位基因以及小鼠的一系列等位基因 突变的Dscam菌株和Dscam同源物Dscam-like 1(Dscaml1)的零等位基因。Dscam和Dscam- Like 1对神经系统的正常发育是必不可少的，Dscam被认为有助于 唐氏综合征的病理学。在视网膜中，Dscam是胞体镶嵌间距所必需的，细胞的调节 数量和轴突的分枝和层叠。我们发表的关于Dscam和Dscaml1的结果是 第一次展示了被发现的破坏马赛克图案的突变，以及第一批被证明参与调节的基因 脊椎动物中的等神经排斥和异神经排斥。具体目标：我们建议使用DSCAM和 Dscaml1突变小鼠模型发现视网膜发育的机制并探索 Dscam在哺乳动物神经系统中的功能。这将通过测试以下各项来实现 本研究方案中详述的假设。假设：1)我们将检验DSCAM假设 利用Dscam小鼠突变系的等位基因序列和条件等位基因介导多种不同的功能 从基因和时间上隔离Dscam依赖的发育过程。2)我们将测试 假设DSCAM调节细胞类型之间的黏附和细胞类型内的排斥，并且 Dscam在视网膜中的活性是由同嗜性相互作用而不是通过配体-受体机制来调节的 通过使用与细胞类型特定缺失相耦合的条件等位基因。3)我们将检验DSCAM的假设 而Dscaml1调控正常的发育细胞死亡。长期目标：这项研究将揭示 神经组织的基本方面，并提供必要的资金，福斯特博士建立一个 成功的学术生涯专注于假说驱动的生物医学研究。 意义：轴突分枝、细胞数量的调节和胞体镶嵌间距是 神经发育的基本方面，目前在分子水平上还没有被很好地理解 脊椎动物。我们的初步研究表明，DSCAM在调节这些过程中起着至关重要的作用 哺乳动物的神经系统。使用一系列鼠标识别DSCAM的工作机制 突变等位基因和条件等位基因将有助于我们理解神经系统的发育和 与神经发育不全相关的疾病的原因，也有助于有价值的研究模型 神经科学界。

ABSTRACT: 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.