Dissecting mechanisms of oligodendrocyte precursor migration

Oligodendrocytes are the myelin-forming cells in the central nervous system (CNS). In the adult CNS oligodendrocytes are ubiquitously distributed, however, oligodendrocyte precursors (OPC) originate from a restricted region in the ventral neural tube and therefore have to migrate long distances to their destination. The regulation of OPC migration is poorly understood. Here, I dissect the molecular mechanisms regulating OPC dispersal and localization in the spinal cord.; Oligodendrocyte precursors originate from the spinal cord ventral ventricular zone, and subsequently migrate radially and dorsally to populate the presumptive white matter. The dispersal of these cells is mediated by a ventral spinal cord (VSC) derived chemorepulsive signal. Coculturing VSC and intermediate spinal cord (ISC) explants resulted in preferential migration of OPCs emerging from ISC explants away from the VSC explants. This VSC-derived chemorepulsive activity can be mimicked by netrin, a floor plate/midline derived guidance cue. Furthermore, OPCs express functional netrin receptors, and the repulsive activity elicited by netrin or VSC explants was abolished by blocking the receptor. These data suggest that netrin constitutes one molecular mechanism that may initiate OPC dispersal from the ventral spinal cord.; OPCs preferentially populate presumptive white matter where they undergo proliferation and differentiation. I demonstrate that the chemokine CXCL1expressed by astrocytes inhibits OPC migration in white matter and in conjunction with platelet-derived growth factor (PDGF) promotes cell proliferation. On purified precursors, CXCL1 exerted a rapid and reversible inhibition of migration in a concentration-dependent fashion. Oligodendrocyte precursors express the CXCL1 chemokine receptor, CXCR2, and the migration arrest was blocked by function-blocking antibodies to CXCR2. In vivo, CXCR2 null mice showed reduced numbers of oligodendrocytes in the spinal cord, and the remaining oligodendrocytes produced a thinner and more peripheral myelination pattern.; Taken together, I propose a model for OPC migration during development in which OPCs are repelled by VSC-derived netrin in the spinal cord to migrate radially and dorsally. Upon reaching, presumptive white matter local expression of CXCL1 arrests OPC migration and positions those cells to receive proliferative stimuli from CXCL1 and PDGF thereby regulating the developmental pattern of spinal cord myelination.