Optimal myelin elongation relies on YAP activation by axonal growth and inhibition by Crb3/Hippo pathway.
Optimal myelin elongation relies on YAP activation by axonal growth and inhibition by Crb3/Hippo pathway.
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DOI：
10.1038/ncomms12186
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发表时间：
2016-07-20
影响因子：
16.6
通讯作者：
Tricaud N
中科院分区：
文献类型：
--
作者：
Fernando RN;Cotter L;Perrin-Tricaud C;Berthelot J;Bartolami S;Pereira JA;Gonzalez S;Suter U;Tricaud N
快速的神经传导依赖于连续的髓鞘节段，这些髓鞘节段电隔离轴突。节段的几何形状--直径和长度--对于神经传导的优化是至关重要的，允许这种优化的几何形状的分子机制是部分已知的。我们在这里表明，外周髓鞘的延长是由轴突延长过程中YAP(Yes-Associated Protein)转录辅助因子活性的刺激而动态调节的，并受到通过河马途径抑制YAP活性的限制。YAP促进髓鞘和非髓鞘基因的转录，而位于髓鞘顶端的极性蛋白Crb3激活河马途径来调节YAP的活性，从而实现最佳的髓鞘生长。营养不良的Dy2j/2J小鼠模仿人类周围神经病，节间长度减少，核Yap减少，当纠正时，导致更长的节间。这些数据显示了一种控制髓鞘生长和神经传导的新机制，并为髓鞘短段疾病提供了分子基础。调节最佳髓鞘构型的分子机制只被部分了解。在这里，作者证明了外周髓鞘的生长是由Crb3/Hippo/YAP途径调控的，YAP激活缺陷可能是由较短的髓鞘引起的外周神经疾病的基础。
Fast nerve conduction relies on successive myelin segments that electrically isolate axons. Segment geometry—diameter and length—is critical for the optimization of nerve conduction and the molecular mechanisms allowing this optimized geometry are partially known. We show here that peripheral myelin elongation is dynamically regulated by stimulation of YAP (Yes-associated protein) transcription cofactor activity during axonal elongation and limited by inhibition of YAP activity via the Hippo pathway. YAP promotes myelin and non-myelin genes transcription while the polarity protein Crb3, localized at the tips of the myelin sheath, activates the Hippo pathway to temper YAP activity, therefore allowing for optimal myelin growth. Dystrophic Dy2j/2j mice mimicking human peripheral neuropathy with reduced internodal lengths have decreased nuclear YAP which, when corrected, leads to longer internodes. These data show a novel mechanism controlling myelin growth and nerve conduction, and provide a molecular ground for disease with short myelin segments. Molecular mechanisms regulating optimal myelin geometry are only partially understood. Here authors show that peripheral myelin growth is orchestrated by the Crb3/Hippo/YAP pathway, and that defects in YAP activation may underlie peripheral neuropathies caused by shorter myelin.