Demographics of Retinal Nerve Cell Populations

视网膜神经细胞群的人口统计学

• 批准号: 9197298
• 负责人: BENJAMIN E REESE
• 金额: $ 38.38万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA BARBARA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9197298
• 关键词: Address; Afferent Neurons; Amacrine Cells; Architecture; Biological Assay; Biological Models; Candidate Disease Gene; Cell Count; Cell Death; Cell Density; Cells; Data; Data Set; Dendrites; Development; Developmental Process; Distal; Electroporation; Foundations; Ganglion Cell Layer; Gene Expression; Genes; Genetic; Genetic Determinism; Genomics; Growth; Harvest; Heritability; In Situ Hybridization; In Vitro; Inbred Strains Mice; Inner Nuclear Layer; Knock-out; Knockout Mice; Lobular; Luciferases; Maps; Measures; Mediating; Messenger RNA; Molecular; Molecular Profiling; Mono-S; Morphology; Mosaicism; Mouse Strains; Mus; Neuronal Differentiation; Neurons; Output; Pattern; Plasmids; Population; Population Dynamics; Positioning Attribute; Quantitative Trait Loci; Recombinant Inbred Strain; Recombinants; Regenerative Medicine; Regulation; Research; Research Proposals; Retina; Retinal; Retinal Diseases; Role; Sampling; Source; Specificity; Statistical Data Interpretation; Stratification; Surface; Synapses; Territoriality; Testing; Tissues; Transcript; Variant; cell type; cholinergic; demographics; developmental disease; genetic variant; horizontal cell; knockout gene; knowledge base; nervous system disorder; neuronal cell body; overexpression; programs; public health relevance; relating to nervous system; response; retinal neuron; trait; transcription factor; transcriptome

 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.

 描述（由申请人提供）：神经元群体在人口统计方面有所不同：它们的绝对数量、细胞间隙和由此产生的模式、树突重叠程度及其调节、突触连接性和与传入神经元相关的收敛比率不同。目前的研究计划一直致力于解决与此类神经元群体动态相关的因果关系，使用视网膜作为模型系统，并与一组由 26 个遗传上不同的重组近交 (RI) 小鼠品系组成的小组合作。对于十二种不同类别的视网膜神经元，这些小鼠品系的神经元数量已显示出很大差异，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），显示基因组共同调控的证据极少。对于每种细胞类型，神经元数量变化的遗传来源将被定义，并且这些基因调节细胞数量的发育作用将被确定。与神经元数量无关，这些 RI 菌株的神经元在其他组织典型特征上有所不同，包括它们在一层内间隔的有序性。水平细胞群体就是这样的一个例子，其中它们的图案有序性的变化映射到两个狭窄的基因组位点。将追寻这些基因座的因果基因及其变异，并对其他细胞类型进行可比较的空间统计分析，以绘制 QTL 图谱，以追寻神经元间距的遗传决定因素。还将检查树突分化时传入神经元和靶神经元数量的这种独立变化的结果，使用 AII 无长突细胞探索其小叶与树突生长的独特独立控制。最后，转录因子 Sox2 在胆碱能无长突细胞中的作用最近已被证明，导致这些无长突细胞在内核层和神经节细胞层之间错位，并将其单层树突转变为双层形态。通过对来自 Sox2 缺陷型视网膜的纯化胆碱能无长突细胞与对照视网膜的纯化胆碱能无长突细胞进行转录组分析，将进一步探索 Sox2 的作用，以确定导致这些改变的胆碱能无长突细胞性状的下游基因。因此，本研究计划将确定视网膜神经元群体人口特征背后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。