Cited by 146Neurogenesis and neuroplasticity mechanismsMultiple Sclerosis Research StudiesNeuroinflammation and Neurodegeneration Mechanisms

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

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Giera, Stefanie, Luo, Rong, Ying, Yanqin, Ackerman, Sarah D, Jeong, Sung-Jin, Stoveken, Hannah M, Folts, Christopher J, Welsh, Christina A +4 more·2018·eLife

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.

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  • Microglia express Transglutaminase 2, which is essential for OPC differentiation.

    “Furthermore, microglia express factors like Transglutaminase 2, which is essential for OPCs differentiation (13).”

    From Acute TREM2 inhibition depletes MAFB-high microglia and hinders remyelination (2025) · cites this paper as [13]

    The Introduction identifies TG2 as microglia-derived and reports that deleting it reduces OPC division and the number of mature oligodendrocytes. The Discussion says the study supports a role in OPC proliferation, while a possible role in OPC differentiation remains for future investigation. Thus, the claim that TG2 is essential for differentiation is not established. (LLM, conf=0.88)

    Experimental — accuracy not yet measured
  • Adgrg1 (Gpr56) is conserved in human, mouse, and zebrafish and is associated with development of oligodendrocytes.

    “Among them is Adgrg1 (Gpr56), demonstrated previously to be conserved in human, mouse, and zebrafish, which is associated with development of oligodendrocytes”
  • Microglia have been previously shown to promote remyelination independent of debris clearance.

    “Whether this prolonged inflammatory response is beneficial for remyelination remains unclear, but microglia have been previously shown to promote remyelination independent of debris clearance55–57.”

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Authors
Giera, S., Luo, R., Ying, Y., Ackerman, S. D., Jeong, S.-J., Stoveken, H. M., Folts, C. J., Welsh, C. A., Tall, G. G., Stevens, B., Monk, K. R., & Piao, X.
Affiliations
  • Boston Children's Hospital (US)
  • University of Oregon (US)
  • University of Michigan (US)
  • Oregon Health & Science University (US)
Corresponding author
  • Monk, Kelly R
  • Piao, Xianhua
Venue
eLife
Published
2018-05-29
Volume
7
ISSN
2050-084X (ISSN-L)
OpenAlex
W2805257681
Cited by
145
References
76
Citations by year
2026: 18 · 2025: 18 · 2024: 19 · 2023: 10 · 2022: 20 · 2021: 20 · 2020: 19 · 2019: 17 · 2018: 2
FWCI
5.33
Type
journal article
Language
en
Open access
Locations
  • eLife (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institute of Neurological Disorders and Stroke (NS085201, NS085201 (R56), NS087801, NS079445)
  • National Multiple Sclerosis Society (FG 2063-A1/2, Harry Weaver Neuroscience Fellowship, RG-1501-02577)
  • National Research Foundation of Korea (2015M3C7A1029037)
  • Ministry of Science, ICT and Future Planning (KBRI Basic Research program 18-BR-02-02)
Topics
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
tissue transglutaminase, ADGRG1, GPR56, oligodendrocyte precursor cells, myelination, remyelination, demyelination, laminin, extracellular matrix, microglia, OPC proliferation
MeSH terms
Oligodendrocyte Precursor Cells, CX3C Chemokine Receptor 1, Remyelination, Protein Glutamine gamma Glutamyltransferase 2, Animals, Cell Differentiation, Cerebellum, Demyelinating Diseases, Female, Humans, Laminin, Male, Oligodendroglia, Transglutaminases, Signal Transduction, Prosencephalon, Microglia, Mice, Knockout, Gene Expression Regulation, Developmental, Cell Lineage, GTP-Binding Proteins, Receptor, Platelet-Derived Growth Factor alpha, Receptors, G-Protein-Coupled, Mice, Neurogenesis

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