title: The thrombin receptor is a critical extracellular switch controlling myelination.
abstract: Hemorrhagic white matter injuries in the perinatal period are a growing cause of cerebral palsy yet no neuroprotective strategies exist to prevent the devastating motor and cognitive deficits that ensue. We demonstrate that the thrombin receptor (protease-activated receptor 1, PAR1) exhibits peak expression levels in the spinal cord at term and is a critical regulator of the myelination continuum from initiation to the final levels achieved. Specifically, PAR1 gene deletion resulted in earlier onset of spinal cord myelination, including substantially more Olig2-positive oligodendrocytes, more myelinated axons, and higher proteolipid protein (PLP) levels at birth. In vitro, the highest levels of PAR1 were observed in oligodendrocyte progenitor cells (OPCs), being reduced with differentiation. In parallel, the expression of PLP and myelin basic protein (MBP), in addition to Olig2, were all significantly higher in cultures of PAR1-/- oligodendroglia. Moreover, application of a small molecule inhibitor of PAR1 (SCH79797) to OPCs in vitro increased PLP and MBP expression. Enhancements in myelination associated with PAR1 genetic deletion were also observed in adulthood as evidenced by higher amounts of MBP and thickened myelin sheaths across large, medium, and small diameter axons. Enriched spinal cord myelination in PAR1-/- mice was coupled to increases in extracellular-signal-regulated kinase 1/2 and AKT signaling developmentally. Nocturnal ambulation and rearing activity were also elevated in PAR1-/- mice. These studies identify the thrombin receptor as a powerful extracellular regulatory switch that could be readily targeted to improve myelin production in the face of white matter injury and disease.
authors: Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, Minnesota; Rehabilitation Medicine Research Center, Mayo Clinic, Rochester, Minnesota.
authors: Hyesook
authors: H
authors: Yoon
authors: Maja
authors: M
authors: Radulovic
authors: Kristen L
authors: KL
authors: Drucker
authors: Jianmin
authors: J
authors: Wu
authors: Isobel A
authors: IA
authors: Scarisbrick
mesh_terms: D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D045604:Extracellular Fluid / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000235:genetics; D009185:Myelin Proteins / Q000235:genetics / Q000378:metabolism*; D009186:Myelin Sheath / Q000378:metabolism*; D009413:Nerve Fibers, Myelinated / Q000378:metabolism / Q000648:ultrastructure; D009457:Neuroglia / Q000378:metabolism; D044463:Receptor, PAR-1 / Q000235:genetics / Q000378:metabolism*; D013234:Stem Cells / Q000378:metabolism
chemical_list: D009185:Myelin Proteins; D044463:Receptor, PAR-1
keywords: G-protein-coupled receptor; myelin basic protein; protease-activated receptor; proteolipid protein; spinal cord development
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