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

适当的大脑发育和功能需要神经干细胞（NSC）在精确的时间，位置和正确的数量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鞘，髓鞘是一种绝缘材料，在有效的神经信息传递中发挥重要作用，并构成大脑白色物质。目前尚不清楚NSC如何形成和维持少突胶质细胞群。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NSC沟通，并通过分泌各种分子指导它们成为少突胶质细胞（Voronova et al. 2017 Neuron）。这些interneuron-secreted分子的确定过剩形成一个骨干资源，推出我的新的长期计划，旨在独特的解剖的基本机制，少突胶质细胞的形成从NSCs.The我目前的建议的目标是开发一个机械的理解，如何interneuron-secreted配体fractalkine（FKN）和肝癌衍生生长因子（HDGF）编排少突胶质细胞的形成从NSCs。目的1：FKN信号转导机制的研究。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适当的少突胶质细胞形成至关重要。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。本研究的目的是探讨FKN如何影响胚胎神经干细胞的信号通路和基因表达，从而导致少突胶质细胞的形成。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形成。本研究旨在探讨胚胎神经干细胞在发育中的脑中形成HDGF少突胶质细胞的作用。目标3：确定FKN是否有必要“>辅助NSC功能。胚胎神经干细胞在成人大脑的一个有趣的区域产生成人神经干细胞，称为脑室下区（SVZ）。这些成体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信号传导在成年NSC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中优先考虑的其他因素。拟议的研究将导致1）在尖端研究和不同职业的可转移技能方面培养高素质人才;和2）对从NSC形成少突胶质细胞的基础生物学的重要科学贡献，用于适当的脑发育和功能。

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.