Astrocytes control the termination of oligodendrocyte precursor cell perivascular migration during CNS development

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PROJECT ABSTRACT: The adult mammalian CNS requires establishment of intricate functional interactions between neurons and glia. Oligodendrocytes (OL), the myelinating cells of the CNS, have critical roles in allowing for rapid saltatory nerve conduction and in maintaining axon integrity. The uniform distribution of OL throughout the adult CNS is therefore critical, but their founder oligodendrocyte progenitor cells (OPCs) arise developmentally from restricted ventricular zone domains in brain and spinal cord. OPCs must undergo an extensive and coordinated migration before halting migration appropriately to differentiate and myelinate their target axons. We have shown for the first time that OPCs distribute through the CNS by migrating on the vasculature, and require the pre-formed scaffold of developed blood vessels as their physical substrate for migration (6, 7). Whilst OPC association with vasculature is critical for their dispersal, equally important for permitting OPC differentiation and proper CNS myelination is the regulation of their appropriate and timely detachment. Indeed we have shown that defective OPC detachment from vasculature blocks their differentiation and can be detrimental to the integrity of the blood brain barrier (8). But how is OPC perivascular migration terminated and co-ordinated with their differentiation? Nothing is known about the regulation of OPC detachment from vasculature at the time of their differentiation. This grant will (1) show that astrocytes co-ordinate the halting of OPC perivascular migration and onset of differentiation by mediating OPC detachment from vasculature, allowing for subsequent OPC differentiation by releasing them from a maturation inhibitory endothelial niche. It will show that an astrocytic Sema3a/6a to OPC Plexin repulsion is the mechanism for releasing OPCs from vessels. It will also (2) answer questions about the mechanisms underlying an OPC’s developmental decision to mature or remain a progenitor, showing that the vasculature is a key player in the extrinsic control of OPC fate decisions and determination of an adult pool of CNS OPCs.