Cadm3 (Necl-1) interferes with the activation of the PI3 kinase/Akt signaling cascade and inhibits Schwann cell myelination in vitro.
Cadm3 (Necl-1) interferes with the activation of the PI3 kinase/Akt signaling cascade and inhibits Schwann cell myelination in vitro.
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DOI：
10.1002/glia.23072
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发表时间：
2016-12
期刊：
影响因子：
6.2
通讯作者：
Maurel, Patrice
中科院分区：
文献类型：
--
作者：
Chen, Ming-Shuo;Kim, Hyosung;Jagot-Lacoussiere, Leonard;Maurel, Patrice
轴突-胶质细胞相互作用对于髓鞘形成和有髓纤维的结构域组织至关重要。属于Cadm家族的细胞粘附分子，特别是Cadm 3（轴突）及其异嗜性结合伴侣Cadm 4（许旺细胞），介导沿着节间的这些相互作用。使用靶向shRNA介导的敲除，我们表明，轴突Cadm 3的去除促进体外DRG神经元/许旺细胞髓鞘形成系统中的许旺细胞髓鞘形成。相反，在DRG神经元轴突表面上过表达Cadm 3导致许旺细胞几乎完全不能形成髓鞘段。与DRG神经元相比，上级颈神经节（SCG）神经元的轴突表达更高水平的Cadm 3，SCG神经元通常不支持雪旺细胞形成髓鞘段。在SCG神经元中敲低Cadm 3促进髓鞘形成。最后，Cadm 3的细胞外结构域以剂量依赖性方式干扰ErbB 3和前髓鞘形成PI 3 K/Akt通路的激活，但不干扰Mek/Erk 1/2通路的激活。虽然没有直接矛盾，但这些体外结果揭示了Cadm 3 −/−小鼠体内研究报告的表型明显缺乏。我们的研究结果表明，Cadm 3可能作为PNS髓鞘形成的负调节，可能通过选择性调节的信号级联激活的雪旺细胞轴突接触，特别是III型NRG-1。需要进一步分析Cadm−/−小鼠的外周神经，以确定轴突Cadm 3在PNS髓鞘形成中的确切作用。
Axo-glial interactions are critical for myelination and the domain organization of myelinated fibers. Cell adhesion molecules belonging to the Cadm family, and in particular Cadm3 (axonal) and its heterophilic binding partner Cadm4 (Schwann cell), mediate these interactions along the internode. Using targeted shRNA-mediated knockdown, we show that the removal of axonal Cadm3 promotes Schwann cell myelination in the in vitro DRG neuron/Schwann cell myelinating system. Conversely, over-expressing Cadm3 on the surface of DRG neuron axons results in an almost complete inability by Schwann cells to form myelin segments. Axons of superior cervical ganglion (SCG) neurons, which do not normally support the formation of myelin segments by Schwann cells, express higher levels of Cadm3 compared to DRG neurons. Knocking down Cadm3 in SCG neurons promotes myelination. Finally, the extracellular domain of Cadm3 interferes in a dose-dependent manner with the activation of ErbB3 and of the pro-myelinating PI3K/Akt pathway, but does not interfere with the activation of the Mek/Erk1/2 pathway. While not in direct contradiction, these in vitro results shed lights on the apparent lack of phenotype that was reported from in vivo studies of Cadm3−/− mice. Our results suggest that Cadm3 may act as a negative regulator of PNS myelination, potentially through the selective regulation of the signaling cascades activated in Schwann cells by axonal contact, and in particular by type III Nrg-1. Further analyses of peripheral nerves in the Cadm−/− mice will be needed to determine the exact role of axonal Cadm3 in PNS myelination.
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DOI：
10.1083/jcb.32.2.439
发表时间：
1967-02
期刊：
The Journal of cell biology
影响因子：
--
作者：
Bunge MB;Bunge RP;Peterson ER;Murray MR
通讯作者：
Murray MR
影响因子：
11.4
作者：
BENLEVY, R;PATERSON, HF;YARDEN, Y
通讯作者：
YARDEN, Y
影响因子：
11.1
作者：
Goebbels, Sandra;Oltrogge, Jan H.;Wolfer, Susanne;Wieser, Georg L.;Nientiedt, Tobias;Pieper, Alexander;Ruhwedel, Torben;Groszer, Matthias;Sereda, Michael W.;Nave, Klaus-Armin
通讯作者：
Nave, Klaus-Armin
影响因子：
4.8
作者：
Kawano, Satoshi;Ikeda, Wataru;Takai, Yoshimi
通讯作者：
Takai, Yoshimi
影响因子：
16.2
作者：
Eshed, Y;Feinberg, K;Peles, E
通讯作者：
Peles, E