Cell surface molecules that require arrangement of retinal neurons and arbors

需要视网膜神经元和乔木排列的细胞表面分子

• 批准号: 8219344
• 负责人: JOSHUA R SANES
• 金额: $ 41.84万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-12-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8219344
• 关键词: Adhesives; Affect; Amacrine Cells; Attention; Binding; Binding Sites; Brain; Caenorhabditis elegans; Cell Surface Proteins; Cell physiology; Cell surface; Cells; Complex; Cues; Cultured Cells; Cytoplasmic Tail; Defect; Dendrites; Development; Drosophila genus; Ectopic Expression; Ensure; Extracellular Domain; Gene Family; Genetic; Homologous Gene; In Vitro; Inner Plexiform Layer; Interneurons; Laboratory culture; Learning; Ligands; Maintenance; Mental disorders; Methods; Modeling; Molecular; Muscle fasciculation; Mutant Strains Mice; Nervous system structure; Neuraxis; Neurites; Neurons; Pattern; Phenotype; Play; Process; Protein Isoforms; Proteins; Retina; Retinal; Retinal Ganglion Cells; Role; Self-control as a personality trait; Signal Transduction; Sorting - Cell Movement; Specificity; Surface; Synapses; System; Testing; Translating; Vertebrates; Visual Fields; Work; avoidance behavior; base; cell type; horizontal cell; in vivo; insight; loss of function; mutant; neural circuit; neuronal cell body; postsynaptic; presynaptic; receptive field; receptor; response; retinal neuron

DESCRIPTION (provided by applicant): Orderly and specific connections among neurons of multiple subtypes underlie the function of neural circuits. Our own work has used retina as a model to elucidate molecules and mechanisms that underlie specificity, focusing on the matching of pre- and postsynaptic partners in particular synaptic laminae. There is another sort of order, however, that has received less attention: the arrangement of cells and their neurites in the orthogonal (x-y) plane. Processes that contribute to this arrangement include mosaic spacing of neuronal somata, tiling of dendrites, and self-avoidance of processes within a single arbor. These processes are believed to ensure uniform coverage of the visual field, precise connectivity, and appropriate receptive field size. Their molecular bases remain unknown in vertebrates. Recently, we began analyzing two sets of cell surface proteins that we suspected to be involved in laminar specificity: MEGF10 and 11, and a cluster of 22 related gamma protocadherins (Pcdhgs). Unexpectedly, preliminary results suggest that both are involved in regulating the arrangement of specific neurons and their dendrites in the x-y plane. Moreover, both affect the same cell type, starburst amacrine cells (SACs), but in different ways: MEGF10/11 regulate the mosaic arrangement of SAC somata whereas Pcdhgs are required for self-avoidance of their dendrites. We will now use these results as starting points to obtain insights into the mechanisms that underlie these common but little-studied aspects of circuit assembly. First, we will use gain- and loss-of function methods in vivo to characterize the role of MEGF10/11 in mosaic formation. We will ask whether MEGF10/11 is effective only during development, whether its effects endure, whether it can disrupt mosaics after they form, and whether the two homologues have distinct effects. Second, we will ask whether defects in self-avoidance observed in conditional Pcdhg mutant mice are cell-autonomous and whether they reflect problems in dendrite formation or refinement. We will then use genetic methods to reduce the repertoire of Pcdhg isoforms that retinal cells express. We can thereby test the role of isoform diversity in the process and learn whether different isoforms play different roles. Third, we will ask whether retinal subtypes other than SACs use MEGF10/11 or Pcdhgs to pattern their somata or arbors. Finally, we will combine studies in vitro and in vivo to initiate analyses of the signaling mechanisms by which MEGF10/11 and Pcdhgs function. We will ask whether MEGF10/11 act as receptors, as ligands, or as both ligand and receptor (that is, homophilically). For Pcdhgs, we will ask how the initially adhesive interaction that Pcdhgs appear to promote is translated into the repellent one required for self-avoidance. Together, these results will further our understanding of two poorly understood gene families and of a poorly understood set of processes important for patterning neural circuits. PUBLIC HEALTH RELEVANCE: Specific connections among myriad neuronal types underlie brain functions, and defects in connectivity underlie some psychiatric disorders. A critical determinant of connectivity is the orderly arrangement of the neurons of each particular type, and of their axonal or dendritic processes. This project uses the retina, a compact and accessible portion of the central nervous system, to analyze two groups of proteins on the neuronal surface that are involved in establishing these arrangements.

描述（由申请人提供）：多个亚型神经元之间有序的和特定的连接是神经回路功能的基础。我们自己的工作已使用视网膜作为模型来阐明特异性构成的分子和机制，重点是特定突触层的突触前和突触后伴侣的匹配。但是，还有另一种秩序受到关注的关注：细胞及其神经突在正交（X-Y）平面中的排列。有助于这种布置的过程包括神经元的镶嵌间距，树突的平铺以及单个植物内的过程的自我避免。人们认为这些过程可确保视野的均匀覆盖范围，精确的连通性和适当的接受场大小。它们的分子碱在脊椎动物中仍然未知。 最近，我们开始分析两组我们怀疑参与层流特异性的细胞表面蛋白：MEGF10和11，以及一个由22个相关伽马蛋白（PCDHGS）组成的簇。出乎意料的是，初步结果表明，两者都参与调节特定神经元及其树突在X-Y平面中的排列。此外，两者都会影响相同的细胞类型，Starburst Amacrine细胞（SAC），但以不同的方式：MEGF10/11调节SAC SOMATA的镶嵌物排列，而PCDHG则需要自避免其树突。现在，我们将将这些结果用作起点，以了解基于电路组装的这些常见但鲜为人知的方面的机制。首先，我们将在体内使用增益和丧失功能方法来表征MEGF10/11在镶嵌形成中的作用。我们将询问MEGF10/11在开发过程中是否有效，其影响是否持续，是否可以在形成后破坏镶嵌物以及两个同源物是否具有明显的影响。其次，我们将询问有条件的PCDHG突变小鼠中观察到的自我避免缺陷是否是细胞自主的，并且它们是否反映了树突形成或细化中的问题。然后，我们将使用遗传方法来减少视网膜细胞表达的PCDHG同工型的曲目。因此，我们可以测试同工型多样性在过程中的作用，并了解不同的同工型是否扮演着不同的角色。第三，我们将询问除SAC以外的视网膜亚型是否使用MEGF10/11或PCDHG对其SOMATA或ARBOR进行模式。最后，我们将在体外和体内结合研究，以启动MEGF10/11和PCDHG功能的信号传导机制的分析。我们将询问MEGF10/11是否充当受体，配体，还是配体和受体（即同型）。对于PCDHG，我们将询问PCDHG似乎促进的最初粘合剂相互作用如何转化为自我避免自我所需的驱虫剂。总之，这些结果将进一步了解我们对两个鲜为人知的基因家族的理解，以及对对神经回路构图重要的一组知识的一组过程。 公共卫生相关性：众多神经元类型之间的具体连接是大脑功能的基础，以及连通性的缺陷是某些精神疾病的基础。连通性的关键决定因素是每种特定类型的神经元及其轴突或树突过程的有序排列。该项目使用视网膜（中枢神经系统的紧凑且可及的部分）来分析与建立这些布置有关的神经元表面上的两组蛋白质。