PDF(Pubmed)
Abstract：
Remyelination after white matter injury (WMI) often fails in diseases such as multiple sclerosis because of improper recruitment and repopulation of oligodendrocyte precursor cells (OPCs) in lesions. How OPCs elicit specific intracellular programs in response to a chemically and mechanically diverse environment to properly regenerate myelin remains unclear. OPCs construct primary cilia, specialized signaling compartments that transduce Hedgehog (Hh) and G-protein-coupled receptor (GPCR) signals. We investigated the role of primary cilia in the OPC response to WMI. Removing cilia from OPCs genetically via deletion of Ift88 results in OPCs failing to repopulate WMI lesions because of reduced proliferation. Interestingly, loss of cilia does not affect Hh signaling in OPCs or their responsiveness to Hh signals but instead leads to dysfunctional cyclic AMP (cAMP)-dependent cAMP response element-binding protein (CREB)-mediated transcription. Because inhibition of CREB activity in OPCs reduces proliferation, we propose that a GPCR/cAMP/CREB signaling axis initiated at OPC cilia orchestrates OPC proliferation during development and in response to WMI.
摘要：
在诸如多发性硬化症的疾病中,由于少突胶质细胞前体细胞(OPCs)的不当募集和再增殖,白质损伤(WMI)后的髓鞘再生常常失败。OPCs如何引发特定的细胞内程序以响应化学和机械上不同的环境以适当地再生髓鞘尚不清楚。OPCs构成初级纤毛，转导Hedgehog（Hh）和G蛋白偶联受体（GPCR）信号的专门信号区室。我们调查了初级纤毛在OPC对WMI的反应中的作用。通过Ift88的缺失从OPCs基因上去除纤毛导致OPCs由于增殖减少而无法重新填充WMI病变。有趣的是,纤毛的丧失不会影响OPCs中的Hh信号或其对Hh信号的反应性，而是导致功能失调的环AMP（cAMP）依赖性cAMP反应元件结合蛋白（CREB）介导的转录。因为抑制OPCs中的CREB活性会减少增殖，我们建议在OPC纤毛处启动的GPCR/cAMP/CREB信号轴可在发育过程中和对WMI的反应中协调OPC的增殖。
