Mirsky Rhona, Woodhoo Ashwin, Parkinson David B, Arthur-Farraj Peter, Bhaskaran Ambily, Jessen Kristján R
Department of Cell and Developmental Biology, University College London, London, UK.
J Peripher Nerv Syst. 2008 Jun;13(2):122-35. doi: 10.1111/j.1529-8027.2008.00168.x.
Immature Schwann cells found in perinatal rodent nerves are generated from Schwann cell precursors (SCPs) that originate from the neural crest. Immature Schwann cells generate the myelinating and non-myelinating Schwann cells of adult nerves. When axons degenerate following injury, Schwann cells demyelinate, proliferate and dedifferentiate to assume a molecular phenotype similar to that of immature cells, a process essential for successful nerve regeneration. Increasing evidence indicates that Schwann cell dedifferentiation involves activation of specific receptors, intracellular signalling pathways and transcription factors in a manner analogous to myelination. We have investigated the roles of Notch and the transcription factor c-Jun in development and after nerve transection. In vivo, Notch signalling regulates the transition from SCP to Schwann cell, times Schwann cell generation, controls Schwann cell proliferation and acts as a brake on myelination. Notch is elevated in injured nerves where it accelerates the rate of dedifferentiation. Likewise, the transcription factor c-Jun is required for Schwann cell proliferation and death and is down-regulated by Krox-20 on myelination. Forced expression of c-Jun in Schwann cells prevents myelination, and in injured nerves, c-Jun is required for appropriate dedifferentiation, the re-emergence of the immature Schwann cell state and nerve regeneration. Thus, both Notch and c-Jun are negative regulators of myelination. The growing realisation that myelination is subject to negative as well as positive controls and progress in molecular identification of negative regulators is likely to impact on our understanding of demyelinating disease and mechanisms that control nerve repair.
在围产期啮齿动物神经中发现的未成熟雪旺细胞由源自神经嵴的雪旺细胞前体（SCPs）产生。未成熟雪旺细胞产生成年神经的髓鞘形成和非髓鞘形成雪旺细胞。当轴突在损伤后退化时，雪旺细胞发生脱髓鞘、增殖和去分化，以呈现与未成熟细胞相似的分子表型，这一过程对于成功的神经再生至关重要。越来越多的证据表明，雪旺细胞去分化涉及特定受体、细胞内信号通路和转录因子的激活，其方式类似于髓鞘形成。我们研究了Notch和转录因子c-Jun在发育过程中和神经横断后的作用。在体内，Notch信号调节从SCP到雪旺细胞的转变，确定雪旺细胞生成的时间，控制雪旺细胞增殖，并对髓鞘形成起制动作用。Notch在损伤神经中升高，加速去分化速率。同样，转录因子c-Jun是雪旺细胞增殖和死亡所必需的，并且在髓鞘形成时被Krox-20下调。在雪旺细胞中强制表达c-Jun可阻止髓鞘形成，在损伤神经中，c-Jun是适当去分化、未成熟雪旺细胞状态的重新出现和神经再生所必需的。因此，Notch和c-Jun都是髓鞘形成的负调节因子。髓鞘形成受到负调控以及正调控这一认识的不断加深，以及负调控因子分子鉴定方面的进展，可能会影响我们对脱髓鞘疾病和控制神经修复机制的理解。
