p38 MAPK activation promotes denervated Schwann cell phenotype and functions as a negative regulator of Schwann cell differentiation and myelination.
p38 MAPK activation promotes denervated Schwann cell phenotype and functions as a negative regulator of Schwann cell differentiation and myelination.
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DOI：
10.1523/jneurosci.5812-11.2012
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发表时间：
2012-05-23
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影响因子：
--
通讯作者：
Kim HA
中科院分区：
文献类型：
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作者：
Yang DP;Kim J;Syed N;Tung YJ;Bhaskaran A;Mindos T;Mirsky R;Jessen KR;Maurel P;Parkinson DB;Kim HA
周围神经的物理损伤在被称为沃勒变性的事件中触发远端神经中的雪旺细胞损伤反应：雪旺细胞降解其髓鞘并去分化，恢复到支持轴突再生和神经修复的表型。调控三叉神经节雪旺细胞可塑性的分子机制尚不清楚。利用体内和体外的周围神经损伤模型，我们发现抑制小鼠周围神经损伤后p38MAPK的活性可以阻止雪旺细胞的脱髓鞘和去分化，这表明该激酶介导了触发远端雪旺细胞损伤反应的损伤信号。在髓鞘共培养中，p38MAPK还介导了神经调节蛋白和成纤维细胞生长因子等雪旺细胞生长因子诱导的髓鞘破坏。此外，p38MAPK的异位激活足以诱导髓鞘破坏，并驱动分化的雪旺细胞获得未成熟雪旺细胞的表型特征。我们还发现p38MAPK同时作为雪旺细胞分化的负性调节因子：增强的p38MAPK激活阻断cAMP诱导的KROX20和髓鞘蛋白的表达，但诱导c-jun的表达。正如预期的那样，p38MAPK在共培养中作为髓鞘形成的负面信号，通过增加单个髓鞘片段的数量和长度来促进髓鞘的形成。总之，我们的数据确认p38MAPK是雪旺细胞可塑性和分化的重要调节因子。
Physical damage to the peripheral nerves triggers Schwann cell injury response in the distal nerves in an event termed Wallerian degeneration: the Schwann cells degrade their myelin sheaths and de-differentiate, reverting to a phenotype that supports axon regeneration and nerve repair. The molecular mechanisms regulating Schwann cell plasticity in the PNS remain to be elucidated. Using both in vivo and in vitro models for peripheral nerve injury, here we show that inhibition of p38 MAPK activity in mice blocks Schwann cell demyelination and de-differentiation following nerve injury, suggesting that the kinase mediates the injury signal that triggers distal Schwann cell injury response. In myelinating co-cultures, p38 MAPK also mediates myelin breakdown induced by Schwann cell growth factors, such as neuregulin and FGF-2. Furthermore, ectopic activation of p38 MAPK is sufficient to induce myelin breakdown and drives differentiated Schwann cells to acquire phenotypic features of immature Schwann cells. We also show that p38 MAPK concomitantly functions as a negative regulator of Schwann cell differentiation: enforced p38 MAPK activation blocks cAMP-induced expression of Krox 20 and myelin proteins, but induces expression of c-Jun. As expected of its role as a negative signal for myelination, inhibition of p38 MAPK in co-cultures promotes myelin formation by increasing the number as well as the length of individual myelin segments. Altogether, our data identify p38 MAPK as an important regulator of Schwann cell plasticity and differentiation.