Abstract

Nerve-glia (NG2) glia or oligodendrocyte precursor cells (OPCs) are distributed throughout the gray and white matter and generate myelinating cells. OPCs in white matter proliferate more than those in gray matter in response to platelet-derived growth factor AA (PDGF AA), despite similar levels of its alpha receptor (PDGFRα) on their surface. Here we show that the type 1 integral membrane protein neuropilin-1 (Nrp1) is expressed not on OPCs but on amoeboid and activated microglia in white but not gray matter in an age- and activity-dependent manner. Microglia-specific deletion of Nrp1 compromised developmental OPC proliferation in white matter as well as OPC expansion and subsequent myelin repair after acute demyelination. Exogenous Nrp1 increased PDGF AA-induced OPC proliferation and PDGFRα phosphorylation on dissociated OPCs, most prominently in the presence of suboptimum concentrations of PDGF AA. These findings uncover a mechanism of regulating oligodendrocyte lineage cell density that involves trans-activation of PDGFRα on OPCs via Nrp1 expressed by adjacent microglia.

Highlights

  • Nerve-glia (NG2) glia or oligodendrocyte precursor cells (OPCs) are distributed throughout the gray and white matter and generate myelinating cells

  • To determine whether the proliferative response of OPCs to platelet-derived growth factor AA (PDGF AA) was modulated by Nrp[1], we tested the effects of anti-Nrp[1] antibody on PDGF AA-induced OPC proliferation in forebrain slice cultures from postnatal day 8 (P8) NG2cre;Z/EG double transgenic mice[15] (Fig. 1A)

  • Since we observed that OPCs were closely apposed to Nrp1+ microglia in P5 corpus callosum as described above (Fig. 2G–I), we investigated whether OPCs that were in contact with Nrp1+ microglia were proliferating more than

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Summary

Introduction

Nerve-glia (NG2) glia or oligodendrocyte precursor cells (OPCs) are distributed throughout the gray and white matter and generate myelinating cells. OPCs in white matter proliferate more than those in gray matter in response to platelet-derived growth factor AA (PDGF AA), despite similar levels of its alpha receptor (PDGFRα) on their surface. Exogenous Nrp[1] increased PDGF AA-induced OPC proliferation and PDGFRα phosphorylation on dissociated OPCs, most prominently in the presence of suboptimum concentrations of PDGF AA. These findings uncover a mechanism of regulating oligodendrocyte lineage cell density that involves trans-activation of PDGFRα on OPCs via Nrp[1] expressed by adjacent microglia. While both cell intrinsic and extrinsic factors influence the differential OPC behavior[16], heterotopic transplantation of 300-μm[3] pieces in slice cultures suggests that the greater proliferative response of OPCs in white matter to PDGF AA is imparted by their local pericellular microenvironment[15]

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