The role of Fat3 in amacrine cell dendrite development.

Fat3 在无长突细胞树突发育中的作用。

基本信息

批准号：
8353135
负责人：
Lisa Goodrich
金额：
$ 21.13万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8353135
关键词：
Address Adopted Amacrine Cells American Apical Automobile Driving Axon Back Behavior Binding Proteins Biochemistry Biological Assay Blindness Brain Cadherins Cataloging Catalogs Cell Surface Receptors Cells DNA Sequence Rearrangement Dendrites Development Electroporation Ensure Environment Event Eye Family Fatty acid glycerol esters Foundations Future Glean Golgi Apparatus Human Image Imaging Techniques In Vitro Individual Inner Plexiform Layer Interneurons Knowledge Label Left Life Ligands Link Location Mediating Molecular Morphogenesis Morphology Movement Mus Neurites Neurons Neuropil Play Population Positioning Attribute Process Proteins Reading Recruitment Activity Resolution Rest Retina Retinal Role Sensory Series Signal Pathway Signal Transduction Staging Stereotyping Synapses System Testing Tissues To specify Vision Visual Work Yeasts axon guidance blind design extracellular improved in vivo member mutant neural prosthesis neuronal cell body novel research study response restoration vasodilator-stimulated phosphoprotein yeast two hybrid system

Address Adopted Amacrine Cells American Apical Automobile Driving Axon Back Behavior Binding Proteins Biochemistry Biological Assay Blindness Brain Cadherins Cataloging Catalogs Cell Surface Receptors Cells DNA Sequence Rearrangement Dendrites Development Electroporation Ensure Environment Event Eye Family Fatty acid glycerol esters Foundations Future Glean Golgi Apparatus Human Image Imaging Techniques In Vitro Individual Inner Plexiform Layer Interneurons Knowledge Label Left Life Ligands Link Location Mediating Molecular Morphogenesis Morphology Movement Mus Neurites Neurons Neuropil Play Population Positioning Attribute Process Proteins Reading Recruitment Activity Resolution Rest Retina Retinal Role Sensory Series Signal Pathway Signal Transduction Staging Stereotyping Synapses System Testing Tissues To specify Vision Visual Work Yeasts axon guidance blind design extracellular improved in vivo member mutant neural prosthesis neuronal cell body novel research study response restoration vasodilator-stimulated phosphoprotein yeast two hybrid system

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项目摘要

DESCRIPTION (provided by applicant): Brain function depends on the flow of information through precisely wired connections between axons and dendrites. Neurons within a circuit can vary widely in the number and arrangement of their dendrites, with some neurons extending only one primary dendrite into a well-defined neuropil and others developing multiple dendrites that extend symmetrically about the cell body. However, in contrast to excellent progress in uncovering mechanisms of axon specification and guidance, relatively little is known about the initial specification and outgrowth of dendrites. In vitro studies suggest that neurons initially extend multipotent neurites, one of which becomes an axon, leaving the remainder to differentiate as dendrites. These results suggest that many aspects of dendrite differentiation are intrinsically regulated. However, in vivo, dendrite development must also be coordinated with the surrounding tissue, such that dendrites are properly positioned to form the appropriate synaptic connections. How extracellular signals induce the intracellular rearrangements that drive the initial specification and subsequent morphogenesis of dendrites is unknown. In the past, this issue has been hard to tackle due to the lack of a suitable assay and the absence of any obvious molecular players. We have been addressing these problems by establishing a system for studying dendrite development in the amacrine cells of the retina. Amacrine cells are typically unipolar, extending a single apical dendrite into a discrete synaptic layer called the inner plexiform layer (IPL). However, in mice lacking the atypical cadherin Fat3, amacrine cells develop a second dendritic arbor that points away from the IPL. Since Fat3 is a cell surface receptor, these results suggest that Fat3 acts by inducing migrating precursors to retract their trailing processes in response to a signal encountered in the IPL. How Fat3 signaling ultimately promotes development of the apical dendrite is a mystery, with no known effectors or ligands. To establish a baseline of knowledge for more detailed analysis of dendrite development, two exploratory studies will be performed. First, we will develop a live imaging assay that can be used to describe the dynamic changes in neurite behavior and Golgi localization that occur as the leading process becomes a dendrite and the trailing process is retracted. Second, to work our way inside the dendrite, we will search for downstream effectors for Fat3, both by testing likely candidate proteins and by performing an unbiased screen for proteins that interact with the Fat3 intracellular domain. Together, these studies will define the salient events of dendrite specification and elucidate the signaling events that occur downstream of Fat3. PUBLIC HEALTH RELEVANCE: Our sense of vision is mediated by precisely organized circuits in the retina, a sensory tissue located at the back of the eye. Millions of Americans are blind and unable to participate in daily activities such as reading and driving. Understanding how visual circuits are wired during development will improve efforts to identify the causes of blindness and eventually design neural prostheses for the restoration of sight.

描述（由申请人提供）：大脑功能取决于通过轴突和树突之间精确有线连接的信息流。电路中的神经元在树突的数量和排列中可能差异很大，有些神经元仅将一个主要的树突延伸到一个定义良好的神经胶质中，而其他神经元则开发了多个木层，这些树突对细胞体的对称延伸。但是，与发现轴突规范和指导的机制中的出色进步相反，对树突的初始规范和产物的了解相对较少。体外研究表明，神经元最初延伸多能神经突，其中一种变成了轴突，其余的是树突的分化。这些结果表明，树突分化的许多方面受到内在调节。但是，在体内，树突发育也必须与周围组织协调，以使树突适当地定位以形成适当的突触连接。细胞外信号如何诱导驱动初始规范和随后的树突形态发生的细胞内重排尚不清楚。过去，由于缺乏合适的测定法和任何明显的分子玩家，因此很难解决这个问题。我们一直在通过建立一个用于研究视网膜的木氨酸细胞中树突发育的系统来解决这些问题。无长熟细胞通常是单极的，将单个顶端树突延伸到一个称为内丛状层（IPL）的离散突触层。然而，在缺乏非典型钙粘蛋白FAT3的小鼠中，无链氨酸细胞会形成第二个树突状乔木，该树枝状乔木远离IPL。由于FAT3是一种细胞表面受体，因此这些结果表明FAT3通过诱导迁移的前体来缩回其尾随过程，以响应IPL中遇到的信号。 FAT3信号传导最终如何促进顶端树突的发展是一个谜，没有已知的效应子或配体。为了建立知识的基准，以对树突开发进行更详细的分析，将进行两项探索性研究。首先，我们将开发一种实时成像测定法，该测定法可以用来描述作为主要过程变成树突的神经突性能和高尔基体定位的动态变化，并缩回了尾随过程。其次，要通过测试可能的候选蛋白质以及对与FAT3细胞内域相互作用的蛋白质进行无偏筛选，我们将通过测试可能的候选蛋白来搜索FAT3的下游效应子。总之，这些研究将定义树突规范的显着事件，并阐明FAT3下游发生的信号传导事件。公共卫生相关性：我们的视力是由视网膜中精确组织的电路介导的，视网膜是一种位于眼后的感觉组织。数以百万计的美国人是盲人，无法参加阅读和驾驶等日常活动。了解在开发过程中的视觉电路如何连接将改善努力确定失明的原因，并最终设计神经假体以恢复视力。