Activated RHOA and peripheral axon regeneration
Activated RHOA and peripheral axon regeneration
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DOI：
10.1016/j.expneurol.2008.04.023
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发表时间：
2008-08-01
影响因子：
5.3
通讯作者：
Zochodne, D. W.
中科院分区：
文献类型：
--
作者：
Cheng, C.;Webber, C. A.;Zochodne, D. W.
成年周围神经元横断后的再生是缓慢的，不完整的，并受到严重障碍的阻碍，无法正常再生。在这种情况下，RHOA GTPase的作用尚未得到研究。我们检测了外周轴突生长过程中RHOA GTPase及其ROK效应物（再生抑制剂）的表达、活性和功能作用。我们采用qRT-PCR、定量免疫组织化学和RHOA激活法检测坐骨横断损伤大鼠感觉神经元的表达。在体外，我们将未在抑制基质上生长的分离的成年感觉神经元暴露于RHOA-ROK抑制剂HA-1077中，并测量了神经突的起始和生长。在体内，我们将早期再生的轴突和雪旺细胞直接暴露于连接横切的坐骨神经近端和远端残端的导管中的HA-1077。完整的成人背根神经节感觉神经元表达RHOA和ROK 1 mrna和蛋白，损伤后RHOA升高。激活的gtp结合的RHOA，在完整的神经节中检测不到，在损伤后神经元和轴突中都显着上调。成年大鼠体外感觉神经元暴露于ROK拮抗剂后，神经突生长的起始和长神经突的比例呈剂量相关增加。直接暴露于ROK抑制剂的再生桥与体内轴突的范围和距离的增加密切相关，并伴有其中的雪旺细胞再生。RHOA的激活和信号传导是成人外周轴突在其自身环境中再生的特征，独立于髓磷脂。抑制其激活可能有利于外周轴突病变。(C) 2008爱思唯尔公司版权所有。
The regeneration of adult Peripheral neurons after transection is slow, incomplete and encumbered by severe barriers to proper regrowth. The role of RHOA GTPase has not been examined in this context. We examined the expression, activity and functional role of RHOA GTPase and its ROK effector, inhibitors of regeneration, during peripheral axon outgrowth. We used qRT-PCR, quantitative immunohistochemistry, and assays of RHOA activation to examine expression in sensory neurons of rats with sciatic transection injuries. In vitro, we exposed dissociated adult sensory neurons, not grown on inhibitory substrates, to a RHOA-ROK inhibitor HA-1077 and measured neurite initiation and outgrowth. In vivo, we exposed early regenerating axons and Schwann cells directly to HA-1077 in a conduit connecting the proximal and distal stumps of transected sciatic nerves. Intact adult dorsal root ganglia sensory neurons expressed RHOA and ROK 1 mRNAs and protein and there were rises in RHOA after injury. Activated GTP-bound RHOA, undetectable in intact ganglia, was dramatically upregulated in both neurons and axons after injury. Adult rat sensory neurons in vitro demonstrated a dose-related increase in the initiation of neurite outgrowth, and in the proportion with long neurites when they were exposed to a ROK antagonist. Regenerative bridges that were directly exposed to the ROK inhibitor had a close-related rise in the extent and distance of in vivo axon and partnered Schwann cell regrowth within them. RHOA activation and signaling are features of adult peripheral axon regeneration within its own milieu, independent of myelin. Inhibition of its activation may benefit peripheral axon lesions. (C) 2008 Elsevier Inc. All rights reserved.