Dlg1, Sec8, and Mtmr2 Regulate Membrane Homeostasis in Schwann Cell Myelination
Dlg1, Sec8, and Mtmr2 Regulate Membrane Homeostasis in Schwann Cell Myelination
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DOI：
10.1523/jneurosci.1423-09.2009
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发表时间：
2009-07-08
影响因子：
5.3
通讯作者：
Bolino, Alessandra
中科院分区：
文献类型：
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作者：
Bolis, Annalisa;Coviello, Silvia;Bolino, Alessandra
如何在髓鞘形成的神经胶质细胞中实现膜生物合成和内稳态大多是未知的。我们以前报道过，肌微管蛋白相关蛋白2（MTMR 2）的丢失引起常染色体隐性脱髓鞘Charcot-Marie-Tooth 4 B1型神经病，其特征是过量的多余髓鞘，也称为髓鞘外折叠。我们产生了Mtmr 2-null小鼠，其模拟人类神经病变。我们还发现，在雪旺细胞中，Mtmr 2与大圆盘1（Dlg 1）相互作用，Dlg 1是一种参与极化贩运和膜添加的支架，其在Mtmr 2-null神经中的定位被改变。我们在这里报告，在雪旺细胞中，Dlg 1还与驱动蛋白13 B（kif 13 B）和Sec 8，这是参与囊泡运输和膜拴系在极化细胞，分别相互作用。利用Mtmr 2-null小鼠作为受损的膜形成的模型，我们在这里提供了第一个证据的机器，在髓鞘形成过程中tiflaminmembrane形成。我们建立了雪旺细胞/DRG神经元共培养Mtmr 2基因敲除小鼠，其中髓鞘外折叠再现，几乎完全获救Mtmr 2替代。通过利用这种体外模型，我们提出了一种机制，即kif 13 B驱动蛋白运输Dlg 1的膜重塑的网站，它协调髓鞘形成的稳态控制。Dlg 1与Sec 8外囊组分的相互作用促进膜添加，而与Mtmr 2，负调节膜形成。因此，髓鞘外折叠是由于髓鞘形成过程中产生的膜量的阴性控制丧失的结果。
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.