Demographics of Retinal Nerve Cell Populations

摘要 神经系统中的细胞群在人口统计学上有所不同：它们的大小、位置、 细胞间距、树突重叠和连通性。这项研究计划一直在识别 这种变异的遗传来源，并分析这些种群动态之间的相互依赖关系， 使用视网膜作为模型系统和26只基因截然不同的重组近交系小鼠 菌株。对于每种不同类型的视网膜，这些品系的小鼠的神经元数量有很大的差异 到目前为止，对神经元进行了分析，这种变异映射到每个细胞的离散的和基本上独立的基因组位置 类型，显示出遗传协同调节的最少证据。本提案将继续探讨 这种细胞数量差异的遗传来源，侧重于不同群体的视网膜中间神经元， 以及它们细胞数量的这种变化如何通过四个新的具体目标影响其他人口统计特征。 具体目标1将扩展我们使用数量性状基因座(QTL)定位策略来识别上位性 控制视网膜细胞数量变化的相互作用。它将在相互作用的基因组中识别候选基因 并直接证明了它们之间的遗传交互作用。《特殊目标2》将研究RBFox基因的作用 视网膜发育中的家族，并在没有RBFox的情况下识别选择性剪接转录本的变化 功能。具体目标3将确定转录因子nfia在选择性控制aII中的作用。 无长突细胞数。它将评估作为发展功能的Nfia的替代拼接，并审查 发育调节亚型的功能特性。具体目标4将定义 VGluT3无长突细胞分化依赖于这些细胞的密度和细胞间距， 试图了解同型相互作用在调节视网膜覆盖率中所起的作用。现在 研究提案将因此确定基因决定因素和细胞间相互作用的基础 视网膜细胞群体的人口学特征。这些研究将澄清我们对视网膜的理解 开发和识别可能导致儿童发育障碍的新基因及其变体 神经系统，共同为再生医学的新兴领域提供信息。

ABSTRACT Cellular populations in the nervous system vary in their demographics: They differ in their size, positioning, intercellular spacing, dendritic overlap, and connectivity. This research program has been identifying the genetic sources of this variation and analyzing the interdependencies between these population dynamics, using the retina as a model system and a panel of twenty-six genetically distinct recombinant inbred mouse strains. Neuron number varies considerably across these strains of mice, for every different type of retinal neuron analyzed to date, and this variation maps to discrete and largely independent genomic loci for each cell type, showing minimal evidence for genetic co-regulation. The present proposal will continue to explore the genetic sources of such variation in cell number, focusing upon different populations of retinal interneurons, and how such variation in their cell number affects those other demographic traits, via four new specific aims. Specific Aim 1 will extend our use of quantitative trait locus (QTL) mapping strategies to identify epistatic interactions controlling the variation in retinal cell number. It will identify candidate genes at interacting genomic loci, and demonstrate their genetic interaction directly. Specific Aim 2 will examine the role of the Rbfox gene family in retinal development, and identify changes in alternative splice transcripts in the absence of RBFOX function. Specific Aim 3 will define the role of the transcription factor, Nfia, in the selective control of AII amacrine cell number. It will assess the alternative splicing of Nfia as a function of development, and examine the functional properties of developmentally regulated isoforms. Specific Aim 4 will define the degree of dependency of VGluT3 amacrine cell differentiation upon the density and intercellular spacing of these cells, seeking to understand the role played by homotypic interactions in regulating retinal coverage. The present research proposal will thereby identify the genetic determinants and intercellular interactions that underlie the demographic features of cellular populations in the retina. These studies will clarify our understanding of retinal development and identify novel genes and their variants that may contribute to developmental disorders of the nervous system, together informing the emerging field of regenerative medicine.