Extracellular matrix dependent maintenance of cortical neuron identity

皮质神经元身份的细胞外基质依赖性维持

• 批准号: 9320519
• 负责人: Aurora Zhang
• 金额: $ 3.65万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9320519
• 关键词: Adult; Affect; Back; Biological Models; Brain; Cells; Cerebral cortex; Cues; Data; Data Set; Development; Disease; Electrophysiology (science); Embryo; Environment; Epigenetic Process; Extracellular Matrix; Extracellular Matrix Degradation; Gene Expression; Gene Expression Profile; Generations; Genes; Genetic Transcription; Goals; Growth Factor; Immunohistochemistry; In Situ Hybridization; Individual; Injury; Knockout Mice; Longevity; Maintenance; Mediating; Mental disorders; Methods; Molecular; Molecular Profiling; Morphology; Natural regeneration; Neocortex; Neuraxis; Neuronal Plasticity; Neurons; Organism; Pathway interactions; Pattern; Play; Population; Property; Role; Signal Transduction; Specificity; Stroke; Synaptic plasticity; Systems Development; Testing; Time; Work; axon regeneration; brain repair; cell type; central nervous system injury; differential expression; experimental study; extracellular; in vivo; inhibitor/antagonist; migration; nervous system disorder; neuron development; neuron loss; postnatal; synaptogenesis; tissue repair; trait; transcriptome sequencing

Project Summary The neocortex contains a great diversity of neuronal subtypes that wire precisely into local and long- distance circuits to execute higher-order functions. To understand the cell-autonomous mechanisms that govern the generation and maintenance of individual classes of neurons, defined neuronal populations have been purified and molecularly profiled across development. However, much less is known about how neurons, once generated, maintain their class-specific traits over long periods of time. Cell intrinsic mechanisms, including transcriptional and epigenetic changes, are being actively studied, yet little is known regarding the role of the extracellular environment. Specifically, the extracellular matrix (ECM) contains many molecules that regulate neuronal function, from migration to synaptogenesis, and its degradation enables synaptic plasticity, wiring, and axonal regeneration, yet little is known about how it influences and is influenced by neuronal identity. Broadly, the goal of this proposal is to understand the contribution of extracellular matrix molecules to the maintenance of neuronal identity. Specifically, I ask: 1. Do different classes of projection neurons produce distinct ECM molecules that help define the molecular composition of their local extracellular microenvironment? 2. Does reprogramming one class of projection neuron into another in vivo result in a change in ECM composition? 3. Does the ECM maintain projection neuron identity through the lifespan of the organism? Here, I propose a set of feasible experiments to explore these questions that builds upon my preliminary data and takes advantage of the expertise of the Arlotta lab. Indeed, my preliminary data already suggests that different subclasses of neurons differentially express ECM-related genes. Answering these questions will reveal a new role for cell-extrinsic cues on neuronal development, highlight an unexplored form of neural plasticity, and pave the way for reprogramming neuronal subtypes in the adult brain, and repairing tissue and circuits upon CNS injury.

项目摘要 新皮层包含了大量的神经元亚型，这些亚型精确地连接到局部和长- 远程电路来执行更高阶的功能。为了理解细胞自主机制， 控制着单个神经元类别的产生和维持，定义的神经元群体具有 在整个发育过程中进行了纯化和分子分析。然而，我们对神经元， 一旦产生，在很长一段时间内保持其类特定的特征。细胞内在机制， 包括转录和表观遗传的变化，正在积极研究，但很少有人知道， 细胞外环境的作用。具体地，细胞外基质（ECM）含有许多分子， 调节神经元功能，从迁移到突触发生，其降解使突触可塑性， 布线和轴突再生，但很少有人知道它是如何影响和影响神经元 身份 广泛地说，这项建议的目标是了解细胞外基质分子对细胞外基质的作用， 神经元身份的维持。具体来说，我问：1。不同种类的投射神经元是否产生 不同的ECM分子，帮助确定其局部细胞外基质的分子组成， 微环境？2.在体内将一类投射神经元重编程为另一类投射神经元是否会导致 ECM成分的变化？3. ECM是否在神经元的整个生命周期中保持投射神经元的身份？ 有机体？在这里，我提出了一套可行的实验，以探索这些问题，建立在我的 初步数据，并利用Arlotta实验室的专业知识。事实上，我的初步数据已经 表明不同亚类的神经元差异表达ECM相关基因。回答这些 这些问题将揭示细胞外部线索在神经元发育中的新作用，突出一种未探索的形式， 神经可塑性，并为成人大脑中的神经元亚型重新编程和修复铺平道路 中枢神经系统损伤后的组织和电路。