Bolis Annalisa, Coviello Silvia, Visigalli Ilaria, Taveggia Carla, Bachi Angela, Chishti Athar H, Hanada Toshihiko, Quattrini Angelo, Previtali Stefano Carlo, Biffi Alessandra, Bolino Alessandra
Dulbecco Telethon Institute, San Raffaele Scientific Institute, 20132 Milan, Italy.
J Neurosci. 2009 Jul 8;29(27):8858-70. doi: 10.1523/JNEUROSCI.1423-09.2009.
How membrane biosynthesis and homeostasis is achieved in myelinating glia is mostly unknown. We previously reported that loss of myotubularin-related protein 2 (MTMR2) provokes autosomal recessive demyelinating Charcot-Marie-Tooth type 4B1 neuropathy, characterized by excessive redundant myelin, also known as myelin outfoldings. We generated a Mtmr2-null mouse that models the human neuropathy. We also found that, in Schwann cells, Mtmr2 interacts with Discs large 1 (Dlg1), a scaffold involved in polarized trafficking and membrane addition, whose localization in Mtmr2-null nerves is altered. We here report that, in Schwann cells, Dlg1 also interacts with kinesin 13B (kif13B) and Sec8, which are involved in vesicle transport and membrane tethering in polarized cells, respectively. Taking advantage of the Mtmr2-null mouse as a model of impaired membrane formation, we provide here the first evidence for a machinery that titrates membrane formation during myelination. We established Schwann cell/DRG neuron cocultures from Mtmr2-null mice, in which myelin outfoldings were reproduced and almost completely rescued by Mtmr2 replacement. By exploiting this in vitro model, we propose a mechanism whereby kif13B kinesin transports Dlg1 to sites of membrane remodeling where it coordinates a homeostatic control of myelination. The interaction of Dlg1 with the Sec8 exocyst component promotes membrane addition, whereas with Mtmr2, negatively regulates membrane formation. Myelin outfoldings thus arise as a consequence of the loss of negative control on the amount of membrane, which is produced during myelination.
在形成髓鞘的神经胶质细胞中，膜生物合成和稳态是如何实现的，目前大多仍不清楚。我们之前报道过，与肌管素相关的蛋白2（MTMR2）缺失会引发常染色体隐性脱髓鞘性遗传性运动感觉神经病4B1型（Charcot-Marie-Tooth type 4B1 neuropathy），其特征是髓鞘过多冗余，也被称为髓鞘折叠。我们构建了一种模拟人类神经病变的Mtmr2基因敲除小鼠。我们还发现，在雪旺细胞中，Mtmr2与盘状大蛋白1（Dlg1）相互作用，Dlg1是一种参与极化运输和膜添加的支架蛋白，其在Mtmr2基因敲除神经中的定位发生了改变。我们在此报告，在雪旺细胞中，Dlg1还与驱动蛋白13B（kif13B）和Sec8相互作用，它们分别参与极化细胞中的囊泡运输和膜拴系。利用Mtmr2基因敲除小鼠作为膜形成受损的模型，我们在此首次提供了一种在髓鞘形成过程中调节膜形成的机制的证据。我们从Mtmr2基因敲除小鼠中建立了雪旺细胞/背根神经节神经元共培养体系，在该体系中髓鞘折叠得以重现，并且通过Mtmr2的替代几乎完全得到了挽救。通过利用这个体外模型，我们提出了一种机制，即kif13B驱动蛋白将Dlg1运输到膜重塑位点，在那里它协调髓鞘形成的稳态控制。Dlg1与Sec8外排复合体成分的相互作用促进膜添加，而与Mtmr2相互作用则对膜形成起负调节作用。因此，髓鞘折叠是髓鞘形成过程中膜量的负调控丧失的结果。
