Microglial transglutaminase-2 drives myelination and myelin repair via GPR56/ADGRG1 in oligodendrocyte precursor cells

Elife. 2018 May 29;7:e33385. doi: 10.7554/eLife.33385.

Abstract

In the central nervous system (CNS), myelin formation and repair are regulated by oligodendrocyte (OL) lineage cells, which sense and integrate signals from their environment, including from other glial cells and the extracellular matrix (ECM). The signaling pathways that coordinate this complex communication, however, remain poorly understood. The adhesion G protein-coupled receptor ADGRG1 (also known as GPR56) is an evolutionarily conserved regulator of OL development in humans, mice, and zebrafish, although its activating ligand for OL lineage cells is unknown. Here, we report that microglia-derived transglutaminase-2 (TG2) signals to ADGRG1 on OL precursor cells (OPCs) in the presence of the ECM protein laminin and that TG2/laminin-dependent activation of ADGRG1 promotes OPC proliferation. Signaling by TG2/laminin to ADGRG1 on OPCs additionally improves remyelination in two murine models of demyelination. These findings identify a novel glia-to-glia signaling pathway that promotes myelin formation and repair, and suggest new strategies to enhance remyelination.

Keywords: microglia; mouse; myelination; neuroscience; oligodendrocyte; remyelination; zebrafish.

Publication types

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

MeSH terms

  • Animals
  • CX3C Chemokine Receptor 1 / genetics
  • CX3C Chemokine Receptor 1 / metabolism
  • Cell Differentiation
  • Cell Lineage / genetics
  • Cerebellum / cytology
  • Cerebellum / metabolism
  • Demyelinating Diseases / genetics*
  • Demyelinating Diseases / metabolism
  • Demyelinating Diseases / pathology
  • Female
  • GTP-Binding Proteins / deficiency
  • GTP-Binding Proteins / genetics*
  • Gene Expression Regulation, Developmental
  • Humans
  • Laminin / genetics
  • Laminin / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Microglia / cytology
  • Microglia / metabolism*
  • Neurogenesis / genetics
  • Oligodendrocyte Precursor Cells / cytology
  • Oligodendrocyte Precursor Cells / metabolism*
  • Oligodendroglia / cytology
  • Oligodendroglia / metabolism*
  • Prosencephalon / cytology
  • Prosencephalon / metabolism
  • Protein Glutamine gamma Glutamyltransferase 2
  • Receptor, Platelet-Derived Growth Factor alpha / genetics
  • Receptor, Platelet-Derived Growth Factor alpha / metabolism
  • Receptors, G-Protein-Coupled / genetics*
  • Receptors, G-Protein-Coupled / metabolism
  • Remyelination / genetics
  • Signal Transduction
  • Transglutaminases / deficiency
  • Transglutaminases / genetics*

Substances

  • CX3C Chemokine Receptor 1
  • Cx3cr1 protein, mouse
  • GPR56 protein, mouse
  • Laminin
  • Receptors, G-Protein-Coupled
  • Protein Glutamine gamma Glutamyltransferase 2
  • Transglutaminases
  • Receptor, Platelet-Derived Growth Factor alpha
  • GTP-Binding Proteins