Institut des Neurosciences de Montpellier, INSERM U1051, University of Montpellier, Hopital Saint Eloi, 80 rue A. Fliche, 34090 Montpellier, France.
ETH, Institute of Molecular Health Sciences, HPL F 36 Otto-Stern-Weg 7, 8093 Zürich, Switzerland.
Nat Commun. 2016 Jul 20;7:12186. doi: 10.1038/ncomms12186.
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 Dy(2j/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.
快速的神经传导依赖于连续的髓鞘节段，这些节段可以使轴突电隔离。节段的几何形状——直径和长度——对于神经传导的优化至关重要，而允许这种优化几何形状的分子机制部分是已知的。我们在这里表明，在外周髓鞘伸长过程中，YAP（Yes 相关蛋白）转录共激活因子活性的刺激可以动态调节 YAP 的活性，而 Hippo 通路通过抑制 YAP 活性来限制 YAP 的活性。YAP 促进髓鞘和非髓鞘基因的转录，而极性蛋白 Crb3 位于髓鞘鞘的尖端，激活 Hippo 通路以抑制 YAP 活性，从而允许髓鞘生长达到最佳状态。模拟人类周围神经病的 Dystrophic Dy(2j/2j) 小鼠具有较短的节间长度，其核内 YAP 减少，当纠正时，会导致更长的节间长度。这些数据显示了一种控制髓鞘生长和神经传导的新机制，并为短髓鞘节段的疾病提供了分子基础。
