MLCK regulates Schwann cell cytoskeletal organization, differentiation and myelination
MLCK regulates Schwann cell cytoskeletal organization, differentiation and myelination
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DOI：
10.1242/jcs.080200
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发表时间：
2011-11-15
影响因子：
4
通讯作者：
Melendez-Vasquez, Carmen V.
中科院分区：
文献类型：
--
作者：
Leitman, Ellen M.;Tewari, Ambika;Melendez-Vasquez, Carmen V.
环磷酸腺苷(CAMP)信号转导参与雪旺细胞(SC)增殖和分化的调控。在静止的干细胞中，cAMP的升高促进了与髓鞘形成相关的蛋白如KROX-20和P0的表达，并下调了与非髓鞘干细胞表型相关的标志物。我们以前已经证明，肌球蛋白II是建立正常的SC-轴突相互作用、分化和髓鞘形成所必需的，然而，这些作用背后的机制尚不清楚。在这里，我们报道了肌球蛋白轻链激酶(MLCK)的水平和活性，一种调节非肌肉细胞中MLC磷酸化的酶，在cAMP处理后在SCs中显著下调，与已知的髓鞘形成抑制剂c-jun的模式相似。在干细胞中敲除MLCK的作用类似于cAMP升高、诱导质膜扩张以及KROX-20和髓鞘蛋白的表达。尽管髓鞘基因转录被激活，但当这些细胞与轴突接触时，它们无法产生致密的髓鞘。我们的数据表明，肌球蛋白II活性在髓鞘形成的不同阶段受到不同程度的调节，在没有MLCK的情况下，SC分化和紧密的髓鞘组装过程是解偶联的。
Signaling through cyclic AMP (cAMP) has been implicated in the regulation of Schwann cell (SC) proliferation and differentiation. In quiescent SCs, elevation of cAMP promotes the expression of proteins associated with myelination such as Krox-20 and P0, and downregulation of markers associated with the non-myelinating SC phenotype. We have previously shown that the motor protein myosin II is required for the establishment of normal SC-axon interactions, differentiation and myelination, however, the mechanisms behind these effects are unknown. Here we report that the levels and activity of myosin light chain kinase (MLCK), an enzyme that regulates MLC phosphorylation in non-muscle cells, are dramatically downregulated in SCs after cAMP treatment, in a similar pattern to that of c-Jun, a known inhibitor of myelination. Knockdown of MLCK in SCs mimics the effect of cAMP elevation, inducing plasma membrane expansion and expression of Krox-20 and myelin proteins. Despite activation of myelin gene transcription these cells fail to make compact myelin when placed in contact with axons. Our data indicate that myosin II activity is differentially regulated at various stages during myelination and that in the absence of MLCK the processes of SC differentiation and compact myelin assembly are uncoupled.