Abstract：
How neuronal signaling affects brain myelination remains poorly understood. We show dysregulated neuronal RHEB-mTORC1-DLK1 axis impairs brain myelination. Neuronal Rheb cKO impairs oligodendrocyte differentiation/myelination, with activated neuronal expression of the imprinted gene Dlk1. Neuronal Dlk1 cKO ameliorates myelination deficit in neuronal Rheb cKO mice, indicating that activated neuronal Dlk1 expression contributes to impaired myelination caused by Rheb cKO. The effect of Rheb cKO on Dlk1 expression is mediated by mTORC1; neuronal mTor cKO and Raptor cKO and pharmacological inhibition of mTORC1 recapitulate elevated neuronal Dlk1 expression. We demonstrate that both a secreted form of DLK1 and a membrane-bound DLK1 inhibit the differentiation of cultured oligodendrocyte precursor cells into oligodendrocytes expressing myelin proteins. Finally, neuronal expression of Dlk1 in transgenic mice reduces the formation of mature oligodendrocytes and myelination. This study identifies Dlk1 as an inhibitor of oligodendrocyte myelination and a mechanism linking altered neuronal signaling with oligodendrocyte dysfunction.
摘要：
神经元信号如何影响脑髓鞘形成仍然知之甚少。我们显示神经元RHEB-mTORC1-DLK1轴失调损害脑髓鞘形成。神经元RhebcKO损害少突胶质细胞分化/髓鞘形成，具有激活的神经元表达的印迹基因Dlk1。神经元Dlk1cKO改善神经元RhebcKO小鼠的髓鞘形成缺陷，表明激活的神经元Dlk1表达有助于由RhebcKO引起的髓鞘形成受损。RhebcKO对Dlk1表达的影响由mTORC1介导；神经元mTorcKO和RaptorcKO以及对mTORC1的药理学抑制概括了神经元Dlk1表达的升高。我们证明了DLK1的分泌形式和膜结合的DLK1均抑制培养的少突胶质细胞前体细胞分化为表达髓磷脂蛋白的少突胶质细胞。最后,转基因小鼠中Dlk1的神经元表达减少了成熟少突胶质细胞的形成和髓鞘形成。这项研究确定了Dlk1是少突胶质细胞髓鞘形成的抑制剂，以及将神经元信号传导改变与少突胶质细胞功能障碍联系起来的机制。
