Glia, 2017-12, Vol.65 (12), p.2070-2086
2017
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Details
- Autor(en) / Beteiligte
- Titel
- Protease activated receptor 2 controls myelin development, resiliency and repair
- Ist Teil von
- Glia, 2017-12, Vol.65 (12), p.2070-2086
- Ort / Verlag
- United States: Wiley Subscription Services, Inc
- Erscheinungsjahr
- 2017
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Oligodendrocytes are essential regulators of axonal energy homeostasis and electrical conduction and emerging target cells for restoration of neurological function. Here we investigate the role of protease activated receptor 2 (PAR2), a unique protease activated G protein‐coupled receptor, in myelin development and repair using the spinal cord as a model. Results demonstrate that genetic deletion of PAR2 accelerates myelin production, including higher proteolipid protein (PLP) levels in the spinal cord at birth and higher levels of myelin basic protein and thickened myelin sheaths in adulthood. Enhancements in spinal cord myelin with PAR2 loss‐of‐function were accompanied by increased numbers of Olig2‐ and CC1‐positive oligodendrocytes, as well as in levels of cyclic adenosine monophosphate (cAMP), and extracellular signal related kinase 1/2 (ERK1/2) signaling. Parallel promyelinating effects were observed after blocking PAR2 expression in purified oligodendrocyte cultures, whereas inhibiting adenylate cyclase reversed these effects. Conversely, PAR2 activation reduced PLP expression and this effect was prevented by brain derived neurotrophic factor (BDNF), a promyelinating growth factor that signals through cAMP. PAR2 knockout mice also showed improved myelin resiliency after traumatic spinal cord injury and an accelerated pattern of myelin regeneration after focal demyelination. These findings suggest that PAR2 is an important controller of myelin production and regeneration, both in the developing and adult spinal cord. Main Points Genetic deletion of PAR2 fosters myelin production developmentally and myelin regeneration in the adult. The promyelinating effects of blocking PAR2 are associated with increases in cAMP, and can be blocked in vitro by inhibiting adenylate cyclase.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0894-1491eISSN: 1098-1136DOI: 10.1002/glia.23215Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5679264
- Format
- –
- Schlagworte
- Adenosine monophosphate, Adenylate cyclase, Animals, Animals, Newborn, Axon guidance, Brain, Brain-derived neurotrophic factor, Brain-Derived Neurotrophic Factor - pharmacology, Clonal deletion, Cyclic AMP, Cyclic AMP - metabolism, Demyelination, development, Electrical conduction, Energy balance, Extracellular signal-regulated kinase, Gene Expression Regulation, Developmental - drug effects, Gene Expression Regulation, Developmental - genetics, Homeostasis, Intracellular Signaling Peptides and Proteins - metabolism, MAP Kinase Signaling System - physiology, Mice, Mice, Transgenic, Myelin, Myelin basic protein, Myelin Basic Protein - genetics, Myelin Basic Protein - metabolism, Myelin proteolipid protein, Myelin Proteolipid Protein - genetics, Myelin Proteolipid Protein - metabolism, Myelin Sheath - physiology, myelination, Nogo Proteins - genetics, Nogo Proteins - metabolism, Olig2 protein, oligodendrocyte, Oligodendrocytes, Oligodendroglia - metabolism, Protease, Proteinase, Proteins, Proteolipid protein, Receptor, PAR-2 - genetics, Receptor, PAR-2 - metabolism, Regeneration, Regulators, remyelination, Repair, Resilience, Restoration, Rodents, Sheaths, Spinal cord, Spinal Cord - cytology, Spinal Cord - growth & development, Spinal cord injuries, Spinal Cord Injuries - metabolism, Spinal Cord Injuries - pathology, Spinal Cord Injuries - physiopathology, Stem Cells - drug effects, Stem Cells - metabolism