Demographics of Retinal Nerve Cell Populations

摘要 神经系统中的细胞群在人口统计学上各不相同：它们的大小、位置、 细胞间距、树突重叠和连通性。这项研究计划已经确定了 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一组26只遗传上不同的重组近交系小鼠 菌株对于每种不同类型的视网膜神经元，这些小鼠品系的神经元数量差异很大。 迄今为止分析的神经元，这种变异映射到每个细胞的离散且基本独立的基因组位点 类型，显示遗传共调节的最小证据。本提案将继续探讨 这种细胞数量变化的遗传来源，集中在视网膜中间神经元的不同群体， 以及细胞数量的变化如何通过四个新的特定目标影响其他人口特征。 具体目标1将扩大我们使用的数量性状基因座（QTL）定位策略，以确定上位性 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， 基因座，并直接展示其遗传相互作用。具体目标2将研究Rbfox基因的作用 家族在视网膜发育中的作用，并确定在没有RBFOX的情况下选择性剪接转录物的变化 功能特异性目标3将定义转录因子Nfia在AII选择性控制中的作用 无长突细胞数。它将评估Nfia的选择性剪接作为发展的一个功能， 发育调节的同种型的功能特性。具体目标4将确定 VGluT3无长突细胞分化依赖于这些细胞的密度和细胞间距， 寻求理解同型相互作用在调节视网膜覆盖中所起的作用。本 因此，研究提案将确定遗传决定因素和细胞间的相互作用， 视网膜中细胞群体的人口统计学特征。这些研究将阐明我们对视网膜病变的认识。 发展和鉴定新的基因及其变异，可能有助于发展障碍的 神经系统，一起通知再生医学的新兴领域。

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.