Genetic approach to the assembly of parallel circuits in the visual system

视觉系统中并行电路组装的遗传方法

基本信息

批准号：
7350170
负责人：
HERWIG BAIER
金额：
$ 37.32万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-03-01 至 2011-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7350170
关键词：
Ablation Address Affect Amacrine Cells Animals Architecture Area Axon Basal lamina Binding Biological Markers Brain Cadherins Cell Adhesion Molecules Cell Communication Cells Characteristics Choline Cholinergic Agents Chromosome Pairing Class Collagen Cues Defect Dendrites Depth Development Diffuse Disease Event Extracellular Matrix Figs - dietary Follow-Up Studies Funding Future Gene Expression Genes Genetic Genetic Screening Grant Growth and Development function Human Image Immunoglobulins Individual Injury Inner Plexiform Layer Label Ligands Light Maintenance Mediating Molecular Mutation Natural regeneration Nature Neurites Neuropil Numbers Organism Outcome POU Domain Parvalbumins Patients Pattern Phenotype Photoreceptors Play Population Positioning Attribute Presynaptic Terminals Process Property Protein Isoforms Proteins Reporter Retina Retinal Retinal Ganglion Cells Role Source Specificity Stratification Structure Synapses Systems Analysis Tectum Mesencephali Testing Therapeutic Tissues Transferase Transgenic Organisms Transplantation Vision Visual Visual system structure Work Zebrafish cell type cholinergic design experience ganglion cell gene discovery horizontal cell interest mutant neural circuit neuronal cell body novel optical imaging outer plexiform layer positional cloning postsynaptic presynaptic protein kinase C gamma receptor research study response retinotectal scaffold segregation superior colliculus Corpora quadrigemina surface coating synaptogenesis transcription factor visual information

项目摘要

DESCRIPTION (provided by applicant): Synapses between cells with similar response properties are often clustered in space and segregated from synapses with different characteristics, giving rise to a layered (or laminar) organization. Little is known about the cellular and molecular mechanisms underlying the precise laminar targeting of axons and dendrites in any brain area. We are using a functional genetic approach in zebrafish to address this question. The inner plexiform layer of the zebrafish retina provides an experimentally tractable system for the analysis of synaptic lamination. Here axons of bipolar and amacrine cell axons form synapses on dendrites of retinal ganglion cells in about ten sublaminae, whose combined synaptic activity represents the visual image. Another important example of laminar architecture is found in the optic tectum. Here axons of individual retinal ganglion cells terminate in only one of four retinorecipient layers. Because we have so far found no evidence in zebrafish that visual experience plays a role in patterning retinal or tectal lamination, our working hypothesis is that these two stratification events are genetically hardwired. Consistent with this hypothesis, we have already identified in forward-genetic screens three zebrafish mutants, moonraker(mra), notorious (noto), and dragnet (drg), each with unique lamination defects in the retina, in the tectum, or in both areas. Using these mutants, we propose to investigate three or possibly four potential mechanisms by which retinal ganglion cells select the correct lamina in which to place their synapses. Aim 1 will ask if homotypic cell-cell interactions are required for laminar targeting of dendrites and axons. Aim 2 will test the role of cholinergic amacrine cells in providing a laminar scaffold for ganglion cell dendrites. Aim 3 will define the exact role of an extracellular matrix component, which we have already identified by positional cloning, in an axon's lamina choice. Aim 4, finally, proposes to identify a novel gene with unknown activity, but strikingly specific mutant phenotype in axon and dendrite lamination. Health-relatedness. Loss of retinal ganglion cells in human patients, through injury or disease, has devastating and currently irreversible consequences for vision. In the future, any therapeutic attempt to stimulate regeneration will not only have to replenish ganglion cells, but also facilitate their integration into the existing synaptic circuitry. This study proposes to identify the molecules that are important for this process during development and growth of the vertebrate organism, thus.

描述（由申请人提供）：具有相似反应特性的细胞之间的突触通常在空间中聚集并与具有不同特征的突触隔离，从而产生分层（或层状）组织。对于任何大脑区域中轴突和树突的精确层状靶向的细胞和分子机制知之甚少。我们正在斑马鱼中使用功能遗传方法来解决这个问题。斑马鱼视网膜的内丛状层为突触分层的分析提供了一个实验上易于处理的系统。这里，双极细胞和无长突细胞轴突在大约十个亚层的视网膜神经节细胞的树突上形成突触，其组合的突触活动代表视觉图像。层状结构的另一个重要例子是在视顶盖中发现的。这里，单个视网膜神经节细胞的轴突仅终止于四个视网膜受体层之一。因为迄今为止我们在斑马鱼中没有发现任何证据表明视觉体验在视网膜或顶盖层状结构中发挥作用，所以我们的工作假设是这两个分层事件在遗传上是硬连线的。与这一假设一致，我们已经在前向遗传筛选中鉴定出三种斑马鱼突变体：moonraker(mra)、notorious(noto)和dragnet(drg)，每种突变体在视网膜、顶盖或两者中都具有独特的层压缺陷地区。使用这些突变体，我们建议研究视网膜神经节细胞选择放置突触的正确层的三种或可能四种潜在机制。目标 1 将询问树突和轴突的层状靶向是否需要同型细胞间相互作用。目标 2 将测试胆碱能无长突细胞在为神经节细胞树突提供层状支架方面的作用。目标 3 将定义细胞外基质成分在轴突层选择中的确切作用，我们已经通过位置克隆鉴定了细胞外基质成分。最后，目标 4 提出鉴定一种活性未知但在轴突和树突层压中具有显着特异性突变表型的新基因。健康相关性。人类患者因受伤或疾病而丧失视网膜神经节细胞，会对视力产生毁灭性且目前不可逆转的后果。未来，任何刺激再生的治疗尝试不仅必须补充神经节细胞，还要促进它们整合到现有的突触回路中。因此，本研究旨在确定在脊椎动物发育和生长过程中对此过程重要的分子。