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

正常的大脑发育和功能需要神经干细胞（NSCs）在精确的时间、地点和数量上产生一种称为少突胶质细胞的特殊类型的细胞。少突胶质细胞的目的是产生髓磷脂，髓磷脂是一种绝缘材料，在有效的神经信息传递中发挥重要作用，并构成脑白质。目前尚不清楚少突胶质细胞群是如何形成和维持的。我的博士后研究结果表明，一种特定类型的脑细胞（中间神经元）通过分泌各种分子与NSCs交流并指示它们成为少突胶质细胞（Voronova et al. 2017 Neuron）。已确定的大量这些中间神经元分泌分子构成了启动我新的长期计划的骨干资源，该计划旨在独特地剖析NSCs形成少突胶质细胞的基本机制。******我目前建议的目标是发展对神经元间分泌配体fractalkine （FKN）和肝癌衍生生长因子（HDGF）如何协调NSCs中少突胶质细胞形成的机制理解。我将用老鼠的前脑作为模型。******目的1：鉴定驱动发育少突胶质细胞形成的FKN信号机制。我的PDF工作确定FKN是一种神经元间分泌的分子，对发育中的大脑皮层中少突胶质细胞的形成至关重要。然而，FKN诱导NSCs少突胶质细胞形成的分子机制尚不清楚。本研究将探讨FKN如何影响胚胎NSCs内导致少突胶质细胞形成的信号通路和基因表达。******目标2：定义HDGF是否是必要的“>发展”。通过额外筛选剩余的神经元间分泌分子，我发现HDGF在培养中诱导少突胶质细胞形成。本研究将探讨胚胎NSCs形成HDGF少突胶质细胞在发育中的作用。******目标3：明确FKN是否需要“>成人NSC功能”。胚胎NSCs在成人大脑中称为心室下区（SVZ）的一个迷人区域产生成人NSCs。这些成人NSCs有助于维持正常成人大脑中的少突胶质细胞群。该目标将确定FKN信号在成人NSCs少突胶质细胞形成中的作用，并为未来研究HDGF和目标2中优先考虑的其他因素优化一个强大的平台。******拟议的研究将导致1)培训高素质人才在尖端研究和各种职业的可转移技能；2)对NSCs形成少突胶质细胞以促进大脑正常发育和功能的基础生物学的重要科学贡献。

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.