Extracellular matrix dependent maintenance of cortical neuron identity

项目摘要 新皮质包含大量不同的神经元亚型，这些亚型精确地连接到局部和长脑皮层. 执行高阶功能的距离电路。要了解细胞自主机制， 管理个别类别神经元的产生和维持，定义的神经元群体有 在发育过程中被提纯并进行分子图谱分析。然而，关于神经元是如何， 一旦产生，就会在很长一段时间内保持其特定于阶级的特征。细胞内在机制， 包括转录和表观遗传的变化，正在积极地研究，但关于 细胞外环境的作用。具体地说，细胞外基质(ECM)包含许多分子， 调节神经元功能，从迁移到突触形成，它的降解使突触可塑性， 连接和轴突再生，但对它如何影响神经元和被神经元影响知之甚少 身份。 概括地说，这项提议的目标是了解细胞外基质分子对 神经元同一性的维持。具体地说，我问：1.不同类别的投射神经元是否会产生 独特的ECM分子，有助于定义其局部细胞外的分子组成 微环境？2.在体内将一类投射神经元重新编程为另一类是否会导致 ECM组成的变化？3.ECM在整个生命周期内是否保持投射神经元的同一性 有机体？在这里，我提出了一系列可行的实验来探索这些问题，这些问题建立在我的 初步数据并利用阿洛塔实验室的专业知识。事实上，我的初步数据已经 提示不同亚类神经元表达ECM相关基因的差异。回答这些问题 问题将揭示细胞的新角色--神经元发育的外在线索，突出一种未知的形式 神经可塑性，并为重新编程成人大脑中的神经元亚型和修复 中枢神经系统损伤后的组织和环路。

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.