The thrombin receptor is a critical extracellular switch controlling myelination.
The thrombin receptor is a critical extracellular switch controlling myelination.
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DOI：
10.1002/glia.22788
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发表时间：
2015-05
期刊：
影响因子：
6.2
通讯作者：
Scarisbrick, Isobel A.
中科院分区：
文献类型：
--
作者：
Yoon, Hyesook;Radulovic, Maja;Drucker, Kristen L.;Wu, Jianmin;Scarisbrick, Isobel A.
关键词：
围产期出血性白色损伤是脑瘫的一个日益增长的原因，但没有神经保护策略存在，以防止随之而来的破坏性运动和认知缺陷。我们证明了凝血酶受体（蛋白酶激活受体1，PAR 1）在脊髓中表现出峰值表达水平，并且是髓鞘形成从开始到最终水平的关键调节剂。具体而言，PAR 1基因缺失导致脊髓髓鞘形成的早期发生，包括出生时显著更多的Olig 2阳性少突胶质细胞、更多的有髓鞘轴突和更高的蛋白脂质蛋白（PLP）水平。在体外，在少突胶质祖细胞（OPC）中观察到最高水平的PAR 1，随着分化而降低。与此同时，PLP和髓鞘碱性蛋白（MBP）的表达，除了Olig 2，在PAR 1 −/−少突胶质细胞的培养物中都显着较高。此外，在体外将PAR 1的小分子抑制剂（SCH 79797）应用于OPCs，抑制PLP和MBP的表达。在成年期也观察到与PAR 1基因缺失相关的髓鞘形成增强，如通过跨越大、中、小直径轴突的更大量的髓鞘碱性蛋白和增厚的髓鞘所证明的。PAR 1 −/−小鼠中丰富的脊髓髓鞘形成与细胞外信号调节激酶1/2和AKT信号的发育增加相关联。PAR 1 −/−小鼠的夜间活动和直立活动也有所增加。这些研究确定凝血酶受体作为一个强大的细胞外调节开关，可以很容易地针对改善髓鞘生产在面对白色物质损伤和疾病。
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.
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影响因子：
6.2
作者：
Burda, Joshua E.;Radulovic, Maja;Yoon, Hyesook;Scarisbrick, Isobel A.
通讯作者：
Scarisbrick, Isobel A.
影响因子：
16.2
作者：
Canoll, PD;Musacchio, JM;Salzer, JL
通讯作者：
Salzer, JL
影响因子：
5.3
作者：
Fortin, D;Rom, E;Bansal, R
通讯作者：
Bansal, R
影响因子：
4.2
作者：
Bansal, R;Magge, S;Winkler, S
通讯作者：
Winkler, S
影响因子：
3.5
作者：
Baron, W;Metz, B;de Vries, H
通讯作者：
de Vries, H