Microglial neuropilin-1 promotes oligodendrocyte expansion during development and remyelination by trans-activating platelet-derived growth factor receptor

Amin Sherafat; Friederike Pfeiffer; Alexander M Reiss; William M Wood; Akiko Nishiyama

doi:10.1038/s41467-021-22532-2

Microglial neuropilin-1 promotes oligodendrocyte expansion during development and remyelination by trans-activating platelet-derived growth factor receptor

Nat Commun. 2021 Apr 15;12(1):2265. doi: 10.1038/s41467-021-22532-2.

Authors

Amin Sherafat¹, Friederike Pfeiffer^{1

2}, Alexander M Reiss¹, William M Wood¹, Akiko Nishiyama^{3

4

5}

Affiliations

¹ Department of Physiology and Neurobiology, University of Connecticut, Storrs, CT, USA.
² Department of Physiology, University of Tübingen, Tübingen, Germany.
³ Department of Physiology and Neurobiology, University of Connecticut, Storrs, CT, USA. [email protected].
⁴ Institute for Systems Genomics, University of Connecticut, Storrs, CT, USA. [email protected].
⁵ The Connecticut Institute for the Brain and Cognitive Sciences, University of Connecticut, Storrs, CT, USA. [email protected].

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Differentiation
Cell Lineage
Cell Proliferation
Cells, Cultured
Cerebellum / cytology
Cerebellum / growth & development
Corpus Callosum / cytology
Corpus Callosum / drug effects
Corpus Callosum / growth & development
Corpus Callosum / pathology
Demyelinating Diseases / chemically induced
Demyelinating Diseases / pathology*
Disease Models, Animal
Female
Humans
Lysophosphatidylcholines / administration & dosage
Lysophosphatidylcholines / toxicity
Male
Mice
Mice, Transgenic
Microglia / drug effects
Microglia / physiology*
Microglia / ultrastructure
Microscopy, Electron, Transmission
Models, Animal
Myelin Sheath / metabolism
Neuropilin-1 / genetics
Neuropilin-1 / metabolism*
Oligodendrocyte Precursor Cells / physiology*
Oligodendroglia / physiology
Platelet-Derived Growth Factor / metabolism
Primary Cell Culture
Receptor, Platelet-Derived Growth Factor alpha / metabolism*
Remyelination*

Substances

Lysophosphatidylcholines
Platelet-Derived Growth Factor
platelet-derived growth factor A
Neuropilin-1
Receptor, Platelet-Derived Growth Factor alpha

Abstract

Publication types

MeSH terms

Substances

Grants and funding