Extrinsic versus intrinsic regulation of oligodendrocyte genesis in the developing and adult brain

大脑的正常发育和功能需要神经干细胞(NSCs)在准确的时间、地点和正确的数量产生一种特殊类型的细胞，称为少突胶质细胞。少突胶质细胞的目的是产生髓鞘，这是一种绝缘材料，在有效的神经信息传输中发挥重要功能，并构成大脑白质。神经干细胞是如何形成和维持少突胶质细胞群体的，目前尚不清楚。我的博士后研究结果显示，一种特定类型的脑细胞(中间神经元)与神经干细胞通信，并通过分泌各种分子指示它们成为少突胶质细胞(Voronova等人)。2017 Neuron)。已确定的过多的这些神经元间分泌分子构成了启动我的新的长期计划的骨干资源，该计划旨在独特地剖析神经干细胞形成少突胶质细胞的基本机制。*我当前提议的目标是从机制上理解中间神经元分泌的配体Fractalkine(FKN)和肝癌衍生生长因子(HDGF)如何协调神经干细胞形成少突胶质细胞。我将使用小鼠前脑作为一个模型。*目标1：识别FKN信号机制，驱动发育中的少突胶质细胞形成。我的PDF研究发现，FKN是一种中间神经元分泌的分子，对发育中的大脑皮层中适当的少突胶质细胞的形成至关重要。然而，FKN如何诱导神经干细胞形成少突胶质细胞的分子机制尚不清楚。本目标将研究FKN如何影响胚胎NSCs中的信号通路和基因表达，从而导致少突胶质细胞的形成。目标2：确定HDGF是否是必需的“&GT；发育。通过对剩余的神经元间分泌分子的额外筛选，我发现HDGF在培养中诱导少突胶质细胞的形成。这个目标将研究胚胎NSCs形成HDGF少突胶质细胞在发育中的脑中的作用。*目标3：确定FKN是否必要”&gt；成年NSC的功能。胚胎神经干细胞在成人大脑中一个令人着迷的区域--脑室下区(SVZ)--成长为成年神经干细胞。这些成年神经干细胞有助于维持正常成人大脑中的少突胶质细胞群。这一目标将确定FKN信号在成年神经干细胞形成少突胶质细胞中的作用，并优化一个强大的平台，用于研究HDGF和未来目标2优先考虑的其他因素。*拟议的研究将导致1)培养具有尖端研究和可移植技能的高素质人员，用于不同职业；2)为神经干细胞形成少突胶质细胞的基础生物学做出重要的科学贡献，以促进脑的正常发育和功能。

Proper brain development and function requires neural stem cells (NSCs) to generate a specialized type of cell termed an oligodendrocyte at precise times, locations and in the right numbers. The purpose of oligodendrocytes is to produce myelin, an insulating material that performs vital functions in efficient neural information transmission and constitutes the brain white matter. How oligodendrocyte populations are formed and maintained by NSCs is currently unclear. Results from my postdoctoral research showed a specific type of brain cell (interneuron) communicates with NSCs and instructs them to become oligodendrocytes by secreting various molecules (Voronova et al. 2017 Neuron). The identified plethora of these interneuron-secreted molecules form a backbone resource to launch my new long-term program that aims to uniquely dissect the fundamental mechanisms of oligodendrocyte formation from NSCs.******The goal of my current proposal is to develop a mechanistic understanding of how interneuron-secreted ligands fractalkine (FKN) and hepatoma derived growth factor (HDGF) orchestrate oligodendrocyte formation from NSCs. I will use the murine forebrain as a model.******OBJECTIVE 1: IDENTIFICATION OF FKN SIGNALLING MECHANISMS DRIVING DEVELOPMENTAL OLIGODENDROCYTE FORMATION. My PDF work identified FKN as an interneuron-secreted molecule critical for proper oligodendrocyte formation in the developing brain cortex. Yet, the molecular mechanism of how FKN induces oligodendrocyte formation from NSCs is unknown. This objective will investigate how FKN affects signalling pathways and gene expression within embryonic NSCs leading to oligodendrocyte formation.******OBJECTIVE 2: DEFINING WHETHER HDGF IS NECESSARY ">DEVELOPMENT. Through additional screening of remaining interneuron-secreted molecules, I discovered HDGF induces oligodendrocyte formation in culture. This objective will investigate the role of HDGF oligodendrocyte formation from embryonic NSCs in the developing brain. ******OBJECTIVE 3: DEFINE WHETHER FKN IS NECESSARY ">ADULT NSC FUNCTION. Embryonic NSCs give rise to adult NSCs in a fascinating area of the adult brain known as the subventricular zone (SVZ). These adult NSCs contribute to the maintenance of oligodendrocyte populations in the normal adult brain. This objective will determine the role of FKN signalling in oligodendrocyte formation from adult NSCs and optimize a powerful platform for studying HDGF and other factors prioritized in Objective 2 in the future.******The proposed research will lead to 1) training of Highly Qualified Personnel in cutting-edge research and transferable skills for diverse careers; and 2) important scientific contributions to fundamental biology of oligodendrocyte formation from NSCs for proper brain development and function.