Dispersion Patterns for Retinal Neuroblasts

描述（由申请人提供）：视网膜的结构复杂性是由一系列控制增殖、命运决定、迁移、过程生长、靶识别、突触发生和细胞死亡的发育事件引起的。这些过程建立了一个精确的分层结构，其中视网膜神经元位于不同的深度，通过两个中间的突触层连接。叠加在这种分层组织上，某些细胞类型以有序阵列的形式分布在给定的层上，以便它们及其过程在与传入和目标神经元建立连接时确保视网膜表面的均匀采样。该研究计划旨在了解这种阵列中的模式和连接性的细胞，分子和遗传决定因素，重点是水平细胞的群体。重组近交系水平细胞数量的定量性状分析将首先确定控制该神经元群体大小的基因。嵌合小鼠将由水平细胞数不同的亲本品系产生，以确定树突状野大小是否受细胞内在指令与环境指令的控制。一个相当的数量性状分析的视锥光感受器也将进行，并在指定树突状图案的水平细胞的传入所发挥的作用将在各种敲除和重组近交系中检查，其中锥细胞和水平细胞之间的收敛比调制，或在这些传入和树突之间的神经传递被改变或废除。由两个同型邻居和传入在建立这种连接所发挥的作用将被确定，检查的假设，即视觉活动的发病驱动相邻的水平细胞之间的竞争性相互作用，因为他们寻求殖民化个别花梗在发展中的外丛状层。来自两个亲本品系的胚胎视网膜的微阵列分析显示水平细胞和视锥细胞数量的两倍差异，将用于鉴定建立这些差异的关键下游基因。这些实验将揭示调节水平和视锥细胞数量的基因，以及水平细胞在发育过程中建立其形态模式、树突覆盖和与视锥传入神经连接的生物学机制。

DESCRIPTION (provided by applicant): The architectural complexity of the retina is brought about by a series of developmental events controlling proliferation, fate determination, migration, process outgrowth, target recognition, synaptogenesis and cell death. These processes establish a precisely layered structure in which retinal neurons become positioned at different depths, connected via two intervening synaptic layers. Superimposed upon this layered organization, certain cell types are distributed as orderly arrays across a given layer so that they, and their processes, ensure a uniform sampling of the retinal surface as they establish connectivity with their afferent and target neurons. This research program is seeking to understand the cellular, molecular and genetic determinants of this patterning and connectivity in such arrays, focusing upon the population of horizontal cells. A quantitative trait analysis of horizontal cell number in recombinant inbred strains will first identify genes that control the size of this neuronal population. Chimeric mice will be produced from parental strains that differ in horizontal cell number, to determine whether dendritic field size is controlled by cell-intrinsic vs. environmental instructions. A comparable quantitative trait analysis of the cone photoreceptors will also be conducted, and the role played by the afferents in specifying dendritic patterning of horizontal cells will be examined in various knockout and recombinant inbred strains in which the convergence ratio between cones and horizontal cells is modulated, or in which neurotransmission between these afferents and the dendrites is altered or abolished. The roles played by both homotypic neighbors and by afferents in the establishment of this connectivity will be determined, examining the hypothesis that the onset of visual activity drives a competitive interaction between neighboring horizontal cells as they seek to colonize individual pedicles in the developing outer plexiform layer. Microarray analysis of embryonic retina from two parental strains showing a two-fold difference in both horizontal and cone cell number will be used to identify downstream genes critical for the establishment of these differences. These experiments will reveal the genes that regulate horizontal and cone cell number, as well as the biological mechanisms by which horizontal cells establish their morphological patterning, dendritic coverage and connectivity with cone afferents during development.