Neuregulin 1-erbB signaling is necessary for normal myelination and sensory function
Neuregulin 1-erbB signaling is necessary for normal myelination and sensory function
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DOI：
10.1523/jneurosci.3785-05.2006
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发表时间：
2006-03-22
影响因子：
5.3
通讯作者：
Corfas, G
中科院分区：
文献类型：
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作者：
Chen, S;Velardez, MO;Corfas, G
为了研究erbB信号传导在外周轴突和髓鞘形成的雪旺细胞之间的相互作用中的作用，我们产生了在这些胶质细胞中表达显性负性erbB受体的转基因小鼠。突变小鼠在成年期有延迟的髓鞘形成，更薄的髓鞘，更短的节间长度和更小的轴突口径。与形态学缺陷一致，转基因小鼠也具有较慢的神经传导速度和对机械刺激的反应缺陷。分子分析表明erbB信号可能通过调节髓鞘基因的转录而促进髓鞘的形成。对坐骨神经的分析表明，突变小鼠的髓鞘基因表达水平降低。体外实验表明，神经调节蛋白-1（NRG 1）诱导髓鞘零蛋白（P0）的表达。此外，我们发现NRG 1对P0表达的影响取决于所使用的NRG 1亚型。当NRG 1在细胞-细胞接触的情况下呈递给雪旺细胞时，III型而不是I型NRG 1调节P0基因表达。这些结果表明，NRG 1- erbB信号通路的中断可能有助于周围神经病与髓鞘形成不足和神经病理性疼痛的发病机制。
To investigate the role of erbB signaling in the interactions between peripheral axons and myelinating Schwann cells, we generated transgenic mice expressing a dominant-negative erbB receptor in these glial cells. Mutant mice have delayed onset of myelination, thinner myelin, shorter internodal length, and smaller axonal caliber in adulthood. Consistent with the morphological defects, transgenic mice also have slower nerve conduction velocity and defects in their responses to mechanical stimulation. Molecular analysis indicates that erbB signaling may contribute to myelin formation by regulating transcription of myelin genes. Analysis of sciatic nerves showed a reduction in the levels of expression of myelin genes in mutant mice. In vitro assays revealed that neuregulin-1 (NRG1) induces expression of myelin protein zero (P0). Furthermore, we found that the effects of NRG1 on P0 expression depend on the NRG1 isoform used. When NRG1 is presented to Schwann cells in the context of cell - cell contact, type III but not type I NRG1 regulates P0 gene expression. These results suggest that disruption of the NRG1 - erbB signaling pathway could contribute to the pathogenesis of peripheral neuropathies with hypomyelination and neuropathic pain.