Hippo regulation of peripheral myelination and nerve repair

摘要 在脊椎动物的外周神经系统中，雪旺细胞（SC）产生隔离大轴突的髓鞘， 使神经冲动得以快速传导髓鞘形成SC具有脱髓鞘的先天能力， 转化为修复性SC，促进创伤性损伤后轴突再生和髓鞘再生。 脱髓鞘也可以发生病理性，并没有有效的治疗方法，以促进或提高 损伤或疾病后的髓鞘再生。发育过程中的髓鞘形成是由几个SC 膜相关蛋白，并要求转录因子Krox 20在细胞核中。然而，在这方面， 我们对髓鞘形成信号在发育过程中如何从细胞膜转移到细胞核知之甚少， 更不用说髓鞘维持和髓鞘再生所需的信号。雅普/TAZ是旁系同源的 具有多种细胞功能的转录辅激活蛋白，最好的已知为细胞的有效启动子， 增殖它们的活性受核质穿梭的调节：当它们在核中时，它们在转录水平上被激活。 活跃我们最近发现，在SC中，雅普/TAZ是核内的，并且是Krox 20表达、髓鞘形成和髓鞘形成所必需的。 表明雅普/TAZ穿梭信号从膜到核调节 髓鞘形成这些发现使我们推测雅普/TAZ是多种信号通路的连接点 导致Krox 20和髓磷脂基因的转录激活，从而调节发育 髓鞘形成、髓鞘维持、脱髓鞘和髓鞘再生。为了验证我们的假设，我们提出了 以下目的：1）确定雅普/TAZ是否介导脱髓鞘和髓鞘再生; 2）鉴定上游 雅普/TAZ在髓鞘形成和维持中的调节剂; 3）确定雅普/TAZ如何调节 Krox 20和髓磷脂基因的转录。我们将使用独特和传统的体外和体内技术， 包括诱导型转基因小鼠的多个品系和RiboTag翻译组分析。拟定研究 这将显著增强我们对SC如何形成、维持和修复外周髓鞘的理解。是 也可能为如何预防脱髓鞘或促进髓鞘再生提供重要的新见解 周围神经疾病

Abstract In the vertebrate peripheral nervous system, Schwann cells (SCs) make myelin that insulates large axons and allows rapid conduction of nerve impulses. Myelinating SCs possess the innate ability to demyelinate and transform into repair SCs, which promote axonal regeneration and remyelination after traumatic injury. Demyelination can also occur pathologically, and there are no effective treatments to promote or enhance remyelination after injury or disease. Myelination during development is triggered by activation of several SC membrane-associated proteins, and requires that the transcription factor Krox20 be in the nucleus. However, we know little about how myelination signals move from the membrane to the nucleus during development and even less about the signaling required for myelin maintenance and remyelination. YAP/TAZ are paralogous transcriptional co-activator proteins with diverse cellular functions, known best as potent promoters of cell proliferation. Their activity is regulated by nucleocytoplasmic shuttling: when nuclear, they are transcriptionally active. We recently showed that in SCs, YAP/TAZ are nuclear and required for Krox20 expression, myelin formation and maintenance, suggesting that YAP/TAZ shuttle signals from membrane to nucleus to regulate myelination. These findings lead us to hypothesize that YAP/TAZ are a nexus for multiple signaling pathways that lead to transcriptional activation of Krox20 and myelin genes, and which thereby regulate developmental myelination, myelin maintenance, demyelination and remyelination. To test our hypothesis, we propose the following Aims: 1) Determine if YAP/TAZ mediate demyelination and remyelination; 2) Identify upstream regulators of YAP/TAZ in myelin formation and maintenance; 3) Determine how YAP/TAZ regulate transcription of Krox20 and myelin genes. We will use unique and conventional in vitro and in vivo techniques, including multiple lines of inducible transgenic mice and RiboTag translatome profiling. The proposed study should significantly enhance our understanding of how SCs form, maintain and repair peripheral myelin. It is also likely to provide important new insights into how to prevent demyelination or promote robust remyelination in peripheral nerve diseases.