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A novel mechanism for synapse localization in the retina

视网膜突触定位的新机制

基本信息

批准号：
10152981
负责人：
Lisa Goodrich
金额：
$ 25.35万
依托单位：
HARVARD MEDICAL SCHOOL
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：
2020-12-01 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10152981
关键词：
Actins Amacrine Cells Back Binding Binding Proteins Binding Sites Biochemical Genetics Biological Assay Bipolar Disorder Brain Cadherins Cell physiology Cells Cellular Assay Complex Cytoskeleton Data Development Drosophila genus Energy Metabolism Extracellular Domain Eye FAT3 gene Family Fatty acid glycerol esters Future Goals Inner Plexiform Layer Interneurons Investigation Location LoxP-flanked allele Mediating Modeling Molecular Mouse Strains Mus Mutant Strains Mice Nature Nervous system structure Neurites Neurodevelopmental Disorder Neurons Neuropil Pathway interactions Pattern Phenotype Photoreceptors Play Process Protein Tyrosine Phosphatase Proteins Retina Retinal Ganglion Cells Role Series Signal Transduction Site Specificity Stains Synapses System Testing Update Vision Work base cell fate specification cell motility conditional knockout experimental study follow-up genetic approach horizontal cell in vivo evaluation innovation migration mouse genetics mutant neural circuit novel outer plexiform layer receptor recruit response retinal damage retinal neuron screening stem cells synaptogenesis vasodilator-stimulated phosphoprotein

项目摘要

PROJECT SUMMARY Neural circuit function depends on the precise organization of diverse types of synapses. In the vertebrate retina, key computations are performed by parallel networks of microcircuits that form highly ordered systems of synapses that are confined to discrete regions of neuropil. For instance, retinal amacrine cells integrate and compute inputs and then communicate this information to retinal ganglion cells via synapses in the inner plexiform layer (IPL). Although we have begun to identify the molecular mechanisms that dictate what type of synapse should form, we still know very little about how synaptic location is controlled. Our long term goal is to define a molecular pathway for synapse localization. The specific objective of this exploratory project is to test the new hypothesis that the atypical cadherin Fat3 determines where synapses will form by harnessing the activity of two known synaptogenic molecules, the WAVE Regulatory Complex (WRC) and the receptor tyrosine phosphatase protein PTPdelta. Data generated during the course of this work will allow us to update our model and develop a more focused investigation of this pathway in the future. Several observations suggest that Fat3 interacts with the WRC and PTP? to control synapse localization in the retina. Fat3 belongs to a family of atypical cadherins with known roles in planar polarity, a signaling system that creates and aligns asymmetries in neighboring cells by creating molecular subdomains (5). The Fat3 intracellular domain harbors multiple binding sites for diverse effectors, including known cytoskeletal regulators and synaptic components, such as the WRC and PTPdelta. Thus, Fat3 is well-suited to respond to signals in neighboring cells and then induce appropriate intracellular responses needed for synapse development. Consistent with this idea, in fat3 mutant mice, retinal amacrine cells show altered patterns of migration and retain extra processes outside of the IPL that go on to form an ectopic plexiform layer (4). Further, by creating and analyzing mice harboring deletions of various regions of the Fat3-ICD, we found that Fat3’s effects on migration and neurite retraction can be separated from its effects on synapse development. Importantly, Fat3-dependent synapse development appears to depend specifically on interactions with the WRC and PTPdelta. The WRC is a well-studied regulator of local changes to the actin cytoskeleton, including at the synapse (12), while PTPdelta is known to be important for synapse development elsewhere in the nervous system (13-15). To follow up on these observations, we will use a combination of biochemical and genetic approaches to characterize physical interactions among Fat3, WRC, and PTP?; test whether retinal synapse development in wild-type and fat3 mutant mice requires WRC function; and determine how Fat3 and PTPdelta influence each other’s distribution and function by examining single and double mutant mouse strains.

项目总结