PMID- 28921694 OWN - NLM STAT- MEDLINE DCOM- 20180605 LR - 20191210 IS - 1098-1136 (Electronic) IS - 0894-1491 (Print) IS - 0894-1491 (Linking) VI - 65 IP - 12 DP - 2017 Dec TI - Protease activated receptor 2 controls myelin development, resiliency and repair. PG - 2070-2086 LID - 10.1002/glia.23215 [doi] AB - 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. CI - (c) 2017 Wiley Periodicals, Inc. FAU - Yoon, Hyesook AU - Yoon H AD - Department of Physical Medicine and Rehabilitation, Rehabilitation Medicine Research Center, Rochester, Minnesota, 55905. AD - Department of Physiology and Biomedical Engineering, Rochester, Minnesota, 55905. FAU - Radulovic, Maja AU - Radulovic M AD - Department of Physical Medicine and Rehabilitation, Rehabilitation Medicine Research Center, Rochester, Minnesota, 55905. AD - Neurobiology of Disease Program, Mayo Clinic, Rochester, Minnesota, 55905. FAU - Walters, Grant AU - Walters G AD - Department of Physical Medicine and Rehabilitation, Rehabilitation Medicine Research Center, Rochester, Minnesota, 55905. FAU - Paulsen, Alex R AU - Paulsen AR AD - Department of Physical Medicine and Rehabilitation, Rehabilitation Medicine Research Center, Rochester, Minnesota, 55905. FAU - Drucker, Kristen AU - Drucker K AD - Department of Physical Medicine and Rehabilitation, Rehabilitation Medicine Research Center, Rochester, Minnesota, 55905. FAU - Starski, Phillip AU - Starski P AD - Neurobiology of Disease Program, Mayo Clinic, Rochester, Minnesota, 55905. FAU - Wu, Jianmin AU - Wu J AD - Department of Physical Medicine and Rehabilitation, Rehabilitation Medicine Research Center, Rochester, Minnesota, 55905. FAU - Fairlie, David P AU - Fairlie DP AD - ARC Centre of Excellence in Advanced Molecular Imaging, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, 4072, Australia. FAU - Scarisbrick, Isobel A AU - Scarisbrick IA AUID- ORCID: 0000-0003-2395-589X AD - Department of Physical Medicine and Rehabilitation, Rehabilitation Medicine Research Center, Rochester, Minnesota, 55905. AD - Department of Physiology and Biomedical Engineering, Rochester, Minnesota, 55905. AD - Neurobiology of Disease Program, Mayo Clinic, Rochester, Minnesota, 55905. LA - eng GR - R01 NS052741/NS/NINDS NIH HHS/United States PT - Journal Article DEP - 20170918 PL - United States TA - Glia JT - Glia JID - 8806785 RN - 0 (Autophagy-Related Proteins) RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Intracellular Signaling Peptides and Proteins) RN - 0 (Myelin Basic Protein) RN - 0 (Myelin Proteolipid Protein) RN - 0 (Nogo Proteins) RN - 0 (Rb1cc1 protein, mouse) RN - 0 (Receptor, PAR-2) RN - E0399OZS9N (Cyclic AMP) SB - IM MH - Animals MH - Animals, Newborn MH - Autophagy-Related Proteins MH - Brain-Derived Neurotrophic Factor/pharmacology MH - Cyclic AMP/metabolism MH - Gene Expression Regulation, Developmental/drug effects/*genetics MH - Intracellular Signaling Peptides and Proteins/metabolism MH - MAP Kinase Signaling System/physiology MH - Mice MH - Mice, Transgenic MH - Myelin Basic Protein/genetics/metabolism MH - Myelin Proteolipid Protein/genetics/metabolism MH - Myelin Sheath/*physiology MH - Nogo Proteins/genetics/metabolism MH - Oligodendroglia/metabolism MH - Receptor, PAR-2/genetics/*metabolism MH - Spinal Cord/*cytology/*growth & development MH - *Spinal Cord Injuries/metabolism/pathology/physiopathology MH - Stem Cells/drug effects/metabolism PMC - PMC5679264 MID - NIHMS903036 OTO - NOTNLM OT - development OT - myelination OT - oligodendrocyte OT - remyelination EDAT- 2017/09/19 06:00 MHDA- 2018/06/06 06:00 PMCR- 2018/12/01 CRDT- 2017/09/19 06:00 PHST- 2017/02/22 00:00 [received] PHST- 2017/08/14 00:00 [revised] PHST- 2017/08/16 00:00 [accepted] PHST- 2017/09/19 06:00 [pubmed] PHST- 2018/06/06 06:00 [medline] PHST- 2017/09/19 06:00 [entrez] PHST- 2018/12/01 00:00 [pmc-release] AID - 10.1002/glia.23215 [doi] PST - ppublish SO - Glia. 2017 Dec;65(12):2070-2086. doi: 10.1002/glia.23215. Epub 2017 Sep 18.