Qki regulates myelinogenesis through Srebp2-dependent cholesterol biosynthesis.
Qki regulates myelinogenesis through Srebp2-dependent cholesterol biosynthesis.
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作者：
Zhou X;Shin S;He C;Zhang Q;Rasband MN;Ren J;Dai C;Zorrilla-Veloz RI;Shingu T;Yuan L;Wang Y;Chen Y;Lan F;Hu J
髓鞘形成依赖于对少突胶质细胞分化和髓鞘形成的及时、精确的控制。胆固醇是髓磷脂中含量最丰富的成分，并且是中枢神经系统中髓磷脂膜组装所必需的。然而，精确控制少突胶质细胞中胆固醇生物合成的潜在机制仍然难以捉摸。在本研究中，我们发现新生小鼠神经干细胞或少突胶质细胞前体细胞中的Qki缺失导致胆固醇生物合成受损和髓鞘生成缺陷，而不影响它们分化为Aspa+Gstpi+髓鞘生成少突胶质细胞。在机制上，Qki-5作为Srebp 2的共激活因子发挥作用，以控制参与少突胶质细胞中胆固醇生物合成的基因的转录。因此，Qki耗竭导致小鼠脑中胆固醇浓度显著降低，损害了适当的髓鞘组装。我们的研究表明，Qki-Srebp 2控制的胆固醇生物合成对于髓鞘形成是不可或缺的，并突出了Qki作为转录共激活剂的新功能，超越了其作为RNA结合蛋白的典型功能。
Myelination depends on timely, precise control of oligodendrocyte differentiation and myelinogenesis. Cholesterol is the most abundant component of myelin and essential for myelin membrane assembly in the central nervous system. However, the underlying mechanisms of precise control of cholesterol biosynthesis in oligodendrocytes remain elusive. In the present study, we found that Qki depletion in neural stem cells or oligodendrocyte precursor cells in neonatal mice resulted in impaired cholesterol biosynthesis and defective myelinogenesis without compromising their differentiation into Aspa+Gstpi+ myelinating oligodendrocytes. Mechanistically, Qki-5 functions as a co-activator of Srebp2 to control transcription of the genes involved in cholesterol biosynthesis in oligodendrocytes. Consequently, Qki depletion led to substantially reduced concentration of cholesterol in mouse brain, impairing proper myelin assembly. Our study demonstrated that Qki-Srebp2-controlled cholesterol biosynthesis is indispensable for myelinogenesis and highlights a novel function of Qki as a transcriptional co-activator beyond its canonical function as an RNA-binding protein.