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 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, inhibited PLP and MBP expression. Enhancements in myelination associated with PAR1 genetic deletion were also observed in adulthood as evidenced by higher amounts of myelin basic protein 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.

Targeting the thrombin receptor modulates inflammation and astrogliosis to improve recovery after spinal cord injury

“…This model produces a severe injury with an initial contusion in addition to a persistent dorsoventral compression resulting in robust inflammation and astrogliosis in addition to axon degeneration (Joshi and Fehlings, 2002; Radulovic et al, 2015). PAR1−/− mice were initially obtained from Jackson Laboratories (Bar Harbor, ME), and backcrossed to C57BL/6 mice for more than 40 generations (Yoon et al, 2015). Uninjured PAR+/+ littermates served as controls.…”

“…PAR1 over activation is linked to vascular disruption (Chen et al, 2010; Liu et al, 2010), neurotoxicity (Smith-Swintosky et al, 1995; Smirnova et al, 1998; Citron et al, 2000; Festoff et al, 2000b; Striggow et al, 2000; Olson et al, 2004; Acharjee et al, 2012; Chen et al, 2012; Yoon et al, 2013), microglial activation (Nishino et al, 1993; Taoka et al, 2000; Xue and Del Bigio, 2001; Suo et al, 2002), astrogliosis (Nishino et al, 1993; Wang et al, 2002b; Sorensen et al, 2003; Olson et al, 2004; Nicole et al, 2005; Vandell et al, 2008), and in the myelination (Yoon et al, 2015) demyelination (Burda et al, 2013) continuum. The thrombin signaling pathway along with PAR1 were identified as among the top pathways activated in primary astrocytes treated with lipopolysaccharide (Zamanian et al, 2012).…”

Interplay between exercise and dietary fat modulates myelinogenesis in the central nervous system

“…NG2 is a chondroitin sulfate proteoglycan that recognizes OPCs in the intact nervous system (Nishiyama et al 2009). Immune localization of each antigen was visualized using standard immunoperoxidase techniques (Yoon et al 2015). Sections immunostained for CC-1 or NG2 were additionally counterstained with methyl green (Vector, Burlingame, CA) to visualize nuclei.…”

Thrombin—unique coagulation system protein with multifaceted impacts on cancer and metastasis

“…Since then, biologically functional receptor has been identified in several human cancer cell types [reviewed in 3, [22][23][24] as well as on metastatic tumors [22]. The thrombin receptor appears to control myelination in development [23], which suggests a potential link to perineural invasion [reviewed in 3,24].…”

“…Several decades ago, pioneering work determined that the Gprotein-coupled thrombin receptor was present on the surface of cancer cells in solid tumors [21], where its contribution to experimental lung metastasis was described [4][5][6][7][8]. Since then, biologically functional receptor has been identified in several human cancer cell types [reviewed in 3, [22][23][24] as well as on metastatic tumors [22]. The thrombin receptor appears to control myelination in development [23], which suggests a potential link to perineural invasion [reviewed in 3,24].…”