Shen Yun-An A, Chen Yan, Dao Dang Q, Mayoral Sonia R, Wu Laiman, Meijer Dies, Ullian Erik M, Chan Jonah R, Lu Q Richard
Department of Neurology and Program in Neurosciences, University of California, San Francisco, California 94158, USA.
1] Department of Pediatrics, Brain Cancer Center, Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229 [2] Department of Pediatrics and Obstetrics/Gynecology, State Key Laboratory of Biotherapy, Cancer Center, West China Second Hospital, Sichuan University, Chengdu 61004, China.
Nat Commun. 2014 Sep 26;5:4991. doi: 10.1038/ncomms5991.
The Schwann cell (SC)-axon interface represents a membrane specialization that integrates axonal signals to coordinate cytoskeletal dynamics resulting in myelination. Here we show that LKB1/Par-4 is asymmetrically localized to the SC-axon interface and co-localizes with the polarity protein Par-3. Using purified SCs and myelinating cocultures, we demonstrate that localization is dependent on the phosphorylation of LKB1 at serine-431. SC-specific deletion of LKB1 significantly attenuates developmental myelination, delaying the initiation and altering the myelin extent into adulthood, resulting in a 30% reduction in the conduction velocity along the adult sciatic nerves. Phosphorylation of LKB1 by protein kinase A is essential to establish the asymmetric localization of LKB1 and Par-3 and rescues the delay in myelination observed in the SC-specific knockout of LKB1. Our findings suggest that SC polarity may coordinate multiple signalling complexes that couple SC-axon contact to the redistribution of specific membrane components necessary to initiate and control myelin extent.
施万细胞（SC）-轴突界面代表一种膜特化结构，它整合轴突信号以协调细胞骨架动力学从而实现髓鞘形成。在此我们表明，LKB1/Par-4不对称定位于SC-轴突界面，并与极性蛋白Par-3共定位。利用纯化的施万细胞和髓鞘形成共培养体系，我们证明这种定位依赖于LKB1丝氨酸431位点的磷酸化。施万细胞特异性缺失LKB1会显著减弱发育性髓鞘形成，延迟髓鞘形成起始并改变成年期的髓鞘范围，导致成年坐骨神经传导速度降低30%。蛋白激酶A对LKB1的磷酸化对于建立LKB1和Par-3的不对称定位至关重要，并挽救了在施万细胞特异性敲除LKB1中观察到的髓鞘形成延迟。我们的研究结果表明，施万细胞极性可能协调多个信号复合物，这些复合物将施万细胞-轴突接触与启动和控制髓鞘范围所需的特定膜成分的重新分布联系起来。
