Microglial neuropilin-1 promotes oligodendrocyte expansion during development and remyelination by trans-activating
Amin Sherafat1, Friederike Pfeiffer1,2, Alexander M Reiss1
1Department of Physiology and Neurobiology, University of Connecticut, Storrs, CT, USA.
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.
Insights
Neuropilin-1 (Nrp1) on microglia enhances oligodendrocyte precursor cell (OPC) proliferation and myelin repair. This interaction boosts OPC expansion and aids myelin regeneration after injury.
Area of Science:
- Neuroscience
- Cell Biology
- Developmental Biology
Background:
- Nerve-glia (NG2) glia, or oligodendrocyte precursor cells (OPCs), are crucial for generating myelinating cells in the central nervous system.
- OPCs in white matter exhibit higher proliferation than those in gray matter in response to platelet-derived growth factor AA (PDGF AA), despite similar PDGFRα receptor levels.
Purpose of the Study:
- To investigate the role of neuropilin-1 (Nrp1) in regulating oligodendrocyte precursor cell (OPC) proliferation and myelin repair.
- To elucidate the interaction between microglia and OPCs in white matter development and repair.
Main Methods:
- Immunohistochemistry to detect Nrp1 expression on microglia in white and gray matter.
- Conditional knockout of Nrp1 in microglia to assess its impact on OPC development and myelin repair.
- In vitro experiments using dissociated OPCs to study the effect of exogenous Nrp1 on PDGF AA-induced proliferation and PDGFRα phosphorylation.
Main Results:
- Neuropilin-1 (Nrp1) is expressed on activated microglia in white matter, but not gray matter, in an age- and activity-dependent manner.
- Microglia-specific deletion of Nrp1 impaired OPC proliferation during development and myelin repair after demyelination.
- Exogenous Nrp1 enhanced PDGF AA-induced OPC proliferation and PDGFRα phosphorylation, particularly at suboptimal PDGF AA concentrations.
Conclusions:
- Nrp1 expressed by microglia plays a critical role in regulating oligodendrocyte lineage cell density.
- Microglial Nrp1 trans-activates PDGFRα on OPCs, promoting their proliferation and contributing to myelin repair.
- This study reveals a novel mechanism involving microglia-glia communication for myelin homeostasis and regeneration.
