Demographics of Retinal Nerve Cell Populations

 描述（由申请人提供）：神经元群体在其人口统计学上各不相同：它们在绝对数量、细胞间间距和由此产生的模式、树突重叠程度及其调节、以及与传入神经元相关的突触连接性和会聚比方面不同。目前的研究计划一直致力于解决与这种神经元群体动力学相关的因果关系，使用视网膜作为模型系统，并与26个遗传上不同的重组近交系（RI）小鼠品系的小组合作。神经元数量在这些品系的小鼠中差异很大，有12种不同类型的视网膜神经元， 这种变异映射到每种细胞类型的离散基因组基因座（数量性状基因座，或QTL），显示基因组共调节的最小证据。将为每种细胞类型定义神经元数量变化的遗传来源，并确定这些基因调节细胞数量的发育作用。独立于神经元数量，神经元在这些RI株的其他组织学特征中不同，包括它们在层内间隔开的有序性。水平细胞群就是这样一个例子，它们模式化的有序性的变化映射到两个狭窄的基因组位点。将追踪这些基因座上的致病基因及其变体，并对其他细胞类型进行可比的空间统计分析，以定位QTL，从而寻找神经元间距的遗传决定因素。树突分化后的传入和靶神经元的数量的这种独立的变化的后果也将被检查，使用AII无长突细胞探索其小叶与树突生长的独特的独立控制。最后，最近已经证明了转录因子Sox 2在胆碱能无长突细胞中的作用，导致这些无长突细胞在内核层和神经节细胞层之间的错误定位，以及它们的单层树突转化为双层形态。Sox 2的作用将被进一步探索，以通过来自Sox 2缺陷与对照视网膜的纯化的胆碱能无长突细胞的转录组谱来鉴定负责这些改变的胆碱能无长突细胞性状的下游基因。因此，本研究提案将确定视网膜神经元群体人口统计学特征的遗传决定因素和细胞间相互作用，澄清我们对视网膜发育的理解，并确定可能导致视网膜疾病的遗传变异。

 DESCRIPTION (provided by applicant): Populations of neurons vary in their demographics: They differ in their absolute numbers, in their intercellular spacing and the patterning this produces, in their degree of dendritic overlap and its regulation, and in their synaptic connectivity and the convergence ratios associated with their afferent neurons. The present research program has been addressing the causal relationships associated with such neuronal population dynamics, using the retina as a model system and working with a panel of twenty-six genetically distinct recombinant inbred (RI) mouse strains. Neuron number has been shown to vary considerably across these strains of mice, for twelve different classes of retinal neuron, and this variation maps to discrete genomic loci (quantitative trait loci, or QTL) for each cell type, showing minimal evidence for genomic co-regulation. The genetic sources of this variation in neuron number will be defined, for each cell type, and the developmental roles of these genes modulating cell number will be identified. Independent of neuron number, neurons vary in other histotypical features across these RI strains, including the orderliness by which they space themselves apart within a layer. The population of horizontal cells is one such example, where variation in the orderliness of their patterning maps to two narrow genomic loci. Causal genes and their variants at these loci will be pursued, and comparable spatial statistical analysis will e conducted for the other cell types to map QTL in pursuit of the genetic determinants of neuronal spacing. The consequence of such independent variation in the number of afferent and target neurons upon dendritic differentiation will also be examined, using the AII amacrine cell to explore the unique independent control of its lobular versus dendritic growth. Finally, a role for the transcription factor Sox2 in cholinergic amacrine cells has recently been demonstrated, causing a mis- positioning of these amacrine cells between the inner nuclear layer and ganglion cell layer, and a conversion of their mono-stratifying dendrites into a bi-stratifying morphology. The role of Sox2 will be further explored to identify the downstream genes responsible for these altered cholinergic amacrine cell traits, by transcriptome- profiling of purified cholinergic amacrine cells from Sox2-deficient versus control retinas. The present research proposal will thereby identify the genetic determinants and intercellular interactions that underlie the demographic features of neuronal populations in the retina, clarifying our understanding of retinal development, as well as identifying genetic variants that may contribute to retinal disease.