Myelination of peripheral nerves is controlled by PI4KB through regulation of Schwann cell Golgi function
Myelination of peripheral nerves is controlled by PI4KB through regulation of Schwann cell Golgi function
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DOI：
10.1073/pnas.2007432117
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发表时间：
2020-11-10
影响因子：
11.1
通讯作者：
Balla, Tamas
中科院分区：
文献类型：
--
作者：
Baba, Takashi;Alvarez-Prats, Alejandro;Balla, Tamas
更好地了解周围神经的髓鞘形成将使周围神经病变（包括腓骨肌萎缩症）患者受益。人们对高尔基腔室在雪旺细胞（SC）功能中的作用知之甚少。在这里，我们通过sc特异性遗传失活磷脂酰肌醇4-激酶β (PI4KB)，一种高尔基相关的脂质激酶，研究了高尔基蛋白在小鼠周围神经髓鞘形成中的作用。这类小鼠坐骨神经轴突的髓磷脂较薄，直径较大，影响Ranvier、Schmidt-Lanterman切口和Cajal带淋巴结的髓磷脂组织明显畸变。非髓鞘SCs明显不能吞噬小直径的神经纤维。突变小鼠的SCs显示高尔基体形态扭曲，顺式高尔基室OSBP消失，整个高尔基体中GOLPH3完全丢失。因此，坐骨神经的胆固醇和鞘磷脂含量大大降低，SCs中观察到的小泡数量也大大减少。虽然突变小鼠的坐骨神经传导速度下降了80%，但小鼠的运动功能仅表现出轻微的损伤。我们的分析表明，PI4KB支持的高尔基功能通过控制脂质代谢、蛋白糖基化和周围神经兰维耶淋巴结微绒毛的组织，对髓鞘形成至关重要。
Better understanding myelination of peripheral nerves would benefit patients affected by peripheral neuropathies, including Charcot-Marie-Tooth disease. Little is known about the role the Golgi compartment plays in Schwann cell (SC) functions. Here, we studied the role of Golgi in myelination of peripheral nerves in mice through SC-specific genetic inactivation of phosphatidylinositol 4-kinase beta (PI4KB), a Golgi-associated lipid kinase. Sciatic nerves of such mice showed thinner myelin of large diameter axons and gross aberrations in myelin organization affecting the nodes of Ranvier, the Schmidt-Lanterman incisures, and Cajal bands. Non-myelinating SCs showed a striking inability to engulf small diameter nerve fibers. SCs of mutant mice showed a distorted Golgi morphology and disappearance of OSBP at the cis-Golgi compartment, together with a complete loss of GOLPH3 from the entire Golgi. Accordingly, the cholesterol and sphingomyelin contents of sciatic nerves were greatly reduced and so was the number of caveolae observed in SCs. Although the conduction velocity of sciatic nerves of mutant mice showed an 80% decrease, the mice displayed only subtle impairment in their motor functions. Our analysis revealed that Golgi functions supported by PI4KB are critically important for proper myelination through control of lipid metabolism, protein glycosylation, and organization of microvilli in the nodes of Ranvier of peripheral nerves.