Demographics of Retinal Nerve Cell Populations

 描述(申请人提供)：神经元群体在其人口统计学上有所不同：它们在绝对数量、细胞间距和由此产生的图案、树突重叠的程度及其调节、突触连接和与其传入神经元相关的会聚比率方面有所不同。目前的研究计划一直在研究与这种神经元种群动态相关的因果关系，使用视网膜作为模型系统，并与26个基因截然不同的重组近交系(RI)小鼠品系合作。在这些品系的小鼠中，12种不同类别的视网膜神经元的神经元数量有很大的不同，并且 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)，显示出基因组共同调节的最小证据。对于每种细胞类型，将确定神经元数量变化的遗传来源，并将识别这些调节细胞数量的基因的发育作用。与神经元数量无关，神经元在这些RI株之间的其他组织典型特征上有所不同，包括它们在一层内分隔自己的有序性。水平细胞群体就是这样一个例子，它们的图案有序性的变化映射到两个狭窄的基因组座位。将追踪这些基因座上的因果基因及其变异，并对其他类型的细胞进行可比的空间统计分析，以定位QTL，以寻求神经元间距的遗传决定因素。使用AII无长突细胞来探索其小叶和树突生长的独特独立控制，也将检验传入神经元和靶神经元数量的这种独立变化对树突分化的影响。最后，最近证实了转录因子Sox2在胆碱能无长突细胞中的作用，导致这些无长突细胞错位在内核层和神经节细胞层之间，并使其单层树突转变为双层形态。SOX2的作用将通过对SOX2缺乏的视网膜和对照视网膜的纯化的胆碱能无长突细胞的转录组谱进一步探索，以确定导致这些改变的胆碱能无长突细胞特征的下游基因。因此，本研究提案将确定构成视网膜神经细胞群体人口统计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基因变异。

 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.