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

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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.