Mek/ERK1/2-MAPK and PI3K/Akt/mTOR signaling plays both independent and cooperative roles in Schwann cell differentiation, myelination and dysmyelination.
Mek/ERK1/2-MAPK and PI3K/Akt/mTOR signaling plays both independent and cooperative roles in Schwann cell differentiation, myelination and dysmyelination.
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作者：
Ishii A;Furusho M;Bansal R
多种信号参与调节许旺细胞的发育髓鞘形成，并在整个成年生活中维持正常的髓鞘稳态，保持PNS中轴突的完整性。最近的研究表明Mek/ERK 1/2-MAPK和PI 3 K/Akt/mTOR细胞内信号通路在PNS髓鞘形成的调节中起重要的作用，通常是重叠的。此外，雪旺细胞中这些信号通路的过度活化导致坐骨神经中各种病理变化的迟发性。然而，它仍然知之甚少，这些途径的功能是否独立或顺序或收敛使用一个共同的机制，以促进雪旺细胞分化和髓鞘生长在发展过程中，并在成年动物引起的病理变化。为了解决这些问题，我们分析了多个转基因小鼠使用同时损失和组成性获得功能的方法。我们发现，在发育过程中，Mek/ERK 1/2-MAPK通路在雪旺细胞分化中起主要作用，与mTOR不同。然而，在活跃的髓鞘形成过程中，ERK 1/2依赖于mTOR信号传导来驱动髓鞘的生长并调节其厚度。最后，我们的数据表明，周围神经病理在成年期引起的过度激活的Mek/ERK 1/2-MAPK或PI 3 K可能是独立的或依赖于mTOR信号在不同的情况下。因此，这项研究强调了两个主要的细胞内信号通路在雪旺氏细胞中发挥的作用的复杂性，影响其分化，髓鞘形成和后来的PNS病理，并预测PNS神经病变中这些通路的潜在治疗调节可能是一个复杂的过程。
Multiple signals are involved in the regulation of developmental myelination by Schwann cells and in the maintenance of a normal myelin homeostasis throughout adult life, preserving the integrity of the axons in the PNS. Recent studies suggest that Mek/ERK1/2-MAPK and PI3K/Akt/mTOR intracellular signaling pathways play important, often overlapping roles in the regulation of myelination in the PNS. In addition, hyperactivation of these signaling pathways in Schwann cells leads to a late onset of various pathological changes in the sciatic nerves. However, it remains poorly understood whether these pathways function independently or sequentially or converge using a common mechanism to facilitate Schwann cell differentiation and myelin growth during development and in causing pathological changes in the adult animals. To address these questions, we analyzed multiple genetically modified mice using simultaneous loss- and constitutive gain-of-function approaches. We found that during development, the Mek/ERK1/2-MAPK pathway plays a primary role in Schwann cell differentiation, distinct from mTOR. However, during active myelination, ERK1/2 is dependent on mTOR signaling to drive the growth of the myelin sheath and regulate its thickness. Finally, our data suggest that peripheral nerve pathology during adulthood caused by hyperactivation of Mek/ERK1/2-MAPK or PI3K is likely to be independent or dependent on mTOR-signaling in different contexts. Thus, this study highlights the complexities in the roles played by two major intracellular signaling pathways in Schwann cells that affect their differentiation, myelination, and later PNS pathology and predicts that potential therapeutic modulation of these pathways in PNS neuropathies could be a complex process.
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影响因子：
6.2
作者：
Figlia G;Gerber D;Suter U
通讯作者：
Suter U
NOTCH1控制脊髓中的少突胶质细胞分化。
影响因子：
7.8
作者：
Genoud, Stephane;Lappe-Siefke, Corinna;Goebbels, Sandra;Radtke, Freddy;Aguet, Michel;Scherer, Steven S;Suter, Ueli;Nave, Klaus-Armin;Mantei, Ned
通讯作者：
Mantei, Ned
DOI：
10.1126/science.1171396
发表时间：
2009-05-15
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Fan HY;Liu Z;Shimada M;Sterneck E;Johnson PF;Hedrick SM;Richards JS
通讯作者：
Richards JS
影响因子：
3.5
作者：
Leone, DP;Genoud, S;Suter, U
通讯作者：
Suter, U
影响因子：
30.8
作者：
Lappe-Siefke, C;Goebbels, S;Nave, KA
通讯作者：
Nave, KA