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Mechanisms Underlying Type II Cadherin Guided Assembly of Retinal Circuits

II 型钙粘蛋白引导视网膜电路组装的潜在机制

基本信息

批准号：
10317067
负责人：
Xin Duan
金额：
$ 39.16万
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：
2020
资助国家：
美国
起止时间：
2020-01-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10317067
关键词：
Address Adopted Anatomy Atlases Axon Biological Assay Biological Models Bipolar Neuron Brain Brain region CRISPR/Cas technology Cadherins Cell Adhesion Molecules Cell Communication Cells Chimeric Proteins Clustered Regularly Interspaced Short Palindromic Repeats Code Complex Defect Detection Development Disease Ensure Etiology Eye Eye diseases Family Genes Genetic Genetic Techniques Goals Individual Injections Interneurons Knowledge Lead Location Logic Mediating Methods Molecular Molecular Profiling Nervous system structure Neuraxis Neurites Neurons Nose Pattern Physiological Positioning Attribute Process Proteins Retina Retinal Ganglion Cells Role Series Signal Transduction Specific qualifier value Specificity Study models Synapses System Testing To specify Translating Vision Visual axon guidance base combinatorial differential expression experimental study extracellular gain of function ganglion cell genetic approach in utero in vivo innovation insight mutant nervous system disorder neural circuit neurodevelopment neuronal patterning novel postsynaptic relating to nervous system retinal neuron segregation starburst amacrine cell synaptogenesis tool visual information

项目摘要

In the eye, complex retinal circuits are wired together for precise neural computation. The diverse but precise wiring between interneurons and retinal ganglion cells serve as the structural basis for circuit processing of different visual features. These parallel circuits are wired up precisely, as defects may lead to several eye diseases and neurological disorders. To investigate the mechanisms behind how diverse neuronal types precisely integrate into distinct parallel retinal circuits, we developed methods that allow for targeted genetic access of the unique On-Off direction-selective circuit, which conveys direction-selectivity signals, as the ideal model system. Our previous studies now position us to examine the role of Type II Cadherins (Cdhs) in assembling this circuit as individual proteins or in combinations. We showed that two Cdhs, Cdh9 and Cdh8, instruct parallel ON and OFF bipolar cell input to ON vs. OFF sublaminae of the ON-OFF direction-selective circuit, thus allowing precise segregation of ON and OFF channels. However, the molecular mechanisms underlying this assembly remain elusive. To investigate the molecular mechanisms underlying the differential functions of Cdh9 vs. Cdh8, we will perform a series of anatomical and functional analyses. We will identify the specific portion of the cadherin molecule, extracellular versus intracellular domains, that are responsible for their distinct functions, as well as the specific timing of their actions in forming synapses between bipolar cells and ganglion cells. We also found that Cdh9 from bipolar neurons heterophilically recognizes the two closely-related Cdhs, Cdh6 and Cdh10, from postsynaptic Ventral-pointing ON-OFF direction-selective ganglion cells (ooDSGCs) and starburst amacrine cells (SACs). We will use this established genetic system to reveal how combinatorial Cdhs act together to wire up parallel direction-selective circuits. We will examine genetically and functionally how Cdh6-9-10 single, double, and triple combinations pattern the Ventral-ooDSGC interaction with SACs. To further expand our understanding of the combinatorial cadherin code in neuronal patterning, we will test the role of Cdh11, which is identified as a Nasal-pointing ooDSGC enriched gene through molecular profiling. Thus, we will generate new molecularly and genetically targeted methods to examine the roles of Cdh11 and its closely related Cdh8 in the wiring of Nasal-pointing direction-selective circuits. Furthermore, we established an in utero injection system to ectopically introduce individual Type II Cdhs onto Ventral-ooDSGCs or Nasal-ooDSGCs to pinpoint combinatorial Cdhs in regulating DS-circuit patterning. Collectively, our studies seek to reveal how Cdh combinations control the formation of parallel but distinct DS circuits. Comprehensive studies on Type II Cdh function would be a major advance for a long-standing question in mammalian neural development. These studies will be a major step forward in understanding how multiple genes interact to specify the wiring of complex neural circuits. The identified mechanisms will have significant relevance to selective circuit wiring throughout the central nervous system.

在眼睛里，复杂的视网膜回路被连接在一起进行精确的神经计算。多样但精确的