Gpr126 Functions in Schwann Cells to Control Differentiation and Myelination via G-Protein Activation
Gpr126 Functions in Schwann Cells to Control Differentiation and Myelination via G-Protein Activation
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DOI：
10.1523/jneurosci.1809-13.2013
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发表时间：
2013-11-13
影响因子：
5.3
通讯作者：
Monk, Kelly R.
中科院分区：
文献类型：
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作者：
Mogha, Amit;Benesh, Andrew E.;Monk, Kelly R.
轴突周围的髓鞘确保神经冲动快速有效地传播，从而使脊椎动物神经系统正常运作。我们以前表明，粘附G蛋白偶联受体（aGPCR）Gpr 126是必不可少的周围神经系统髓鞘，虽然Gpr 126功能的分子机制还不完全清楚。aGPCR是一种明显研究不足的蛋白质类别，并且不知道Gpr 126是否与G蛋白偶联。在这里，我们分析了Dhh（Cre）; Gpr 126（fl/fl）条件突变体，并显示Gpr 126在雪旺细胞（SC）中的功能，用于轴突的径向分选和髓鞘形成。此外，我们表明，cAMP水平或蛋白激酶A激活的升高抑制髓鞘缺陷的Gpr 126小鼠突变体和cAMP水平降低条件Gpr 126突变体外周神经。最后，我们发现GPR 126通过偶联异源三聚体G蛋白直接增加cAMP。总之，这些数据支持了一个模型，其中Gpr 126在SC中发挥作用，以促进正常发育和髓鞘形成，并提供证据表明这些功能是通过G蛋白信号通路介导的。
The myelin sheath surrounding axons ensures that nerve impulses travel quickly and efficiently, allowing for the proper function of the vertebrate nervous system. We previously showed that the adhesion G-protein-coupled receptor (aGPCR) Gpr126 is essential for peripheral nervous system myelination, although the molecular mechanisms by which Gpr126 functions were incompletely understood. aGPCRs are a significantly understudied protein class, and it was unknown whether Gpr126 couples to G-proteins. Here, we analyze Dhh(Cre); Gpr126(fl/fl) conditional mutants, and show that Gpr126 functions in Schwann cells (SCs) for radial sorting of axons and myelination. Furthermore, we demonstrate that elevation of cAMP levels or protein kinase A activation suppresses myelin defects in Gpr126 mouse mutants and that cAMP levels are reduced in conditional Gpr126 mutant peripheral nerve. Finally, we show that GPR126 directly increases cAMP by coupling to heterotrimeric G-proteins. Together, these data support a model in which Gpr126 functions in SCs for proper development and myelination and provide evidence that these functions are mediated via G-protein-signaling pathways.