Microglial transglutaminase-2 drives myelination and myelin repair via GPR56/ADGRG1 in oligodendrocyte precursor cells
- Boston Children's Hospital, United States
- Washington University School of Medicine, United States
- University of Michigan Medical Center, United States
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 ADGRG1) 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.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files.
Article and author information
Author details
Christopher J Folts
Funding
National Institute of Neurological Disorders and Stroke (NS094164)
- Xianhua Piao
National Multiple Sclerosis Society (RG-1501-02577)
- Xianhua Piao
National Institute of Neurological Disorders and Stroke (NS08520)
- Xianhua Piao
National Institute of Neurological Disorders and Stroke (NS079445)
- Kelly R Monk
National Multiple Sclerosis Society (FG 2063-A1/2)
- Stefanie Giera
National Multiple Sclerosis Society (Harry Weaver Neuroscience Fellowship)
- Kelly R Monk
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in accordance to the guidelines of the Animal Care and Use Committee (IACUC) protocols (17-12-3578R and 17-03-3378R) at Boston Children's Hospital. Zebrafish experiments were performed in compliance with Washington University's Institutional Animal Care and Use Committee (IACUC) protocol (20160174)
Reviewing Editor
- Klaus-Armin Nave, Max Planck Institute for Experimental Medicine, Germany
Publication history
- Received: November 6, 2017
- Accepted: May 18, 2018
- Accepted Manuscript published: May 29, 2018 (version 1)
- Version of Record published: May 31, 2018 (version 2)
Copyright
© 2018, Giera et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Microglial transglutaminase-2 drives myelination and myelin repair via GPR56/ADGRG1 in oligodendrocyte precursor cells
eLife 7:e33385.
https://doi.org/10.7554/eLife.33385
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