Disruption of neuronal RHEB signaling impairs oligodendrocyte differentiation and myelination through mTORC1-DLK1 axis
Disruption of neuronal RHEB signaling impairs oligodendrocyte differentiation and myelination through mTORC1-DLK1 axis
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DOI：
10.1016/j.celrep.2023.112801
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发表时间：
2023-07-17
期刊：
影响因子：
8.8
通讯作者：
Xiao，Bo
中科院分区：
文献类型：
--
作者：
Huang，Haijiao;Jing，Bo;Xiao，Bo
神经元信号如何影响大脑髓鞘形成仍然知之甚少。我们发现神经元 RHEB-mTORC1-DLK1 轴失调会损害脑髓鞘形成。 NeuronalRhebcKO 会损害少突胶质细胞分化/髓鞘形成，并激活印迹基因 Dlk1 的神经元表达。 NeuronalDlk1cKO 改善了 NeuronalRhebcKO 小鼠的髓鞘形成缺陷，表明激活的神经元 Dlk1 表达有助于 RhebcKO 引起的髓鞘形成受损。 RhebcKO对Dlk1表达的影响是由mTORC1介导的；神经元TorcKO和RaptorcKO以及mTORC1的药理学抑制概括了神经元Dlk1表达的升高。我们证明，分泌形式的 DLK1 和膜结合的 DLK1 都会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 Dlk1 是少突胶质细胞髓鞘形成的抑制剂，也是一种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。
How neuronal signaling affects brain myelination remains poorly understood. We show dysregulated neuronal RHEB-mTORC1-DLK1 axis impairs brain myelination. NeuronalRhebcKO impairs oligodendrocyte differentiation/myelination, with activated neuronal expression of the imprinted geneDlk1. NeuronalDlk1cKO ameliorates myelination deficit in neuronalRhebcKO mice, indicating that activated neuronalDlk1expression contributes to impaired myelination caused byRhebcKO. The effect ofRhebcKO onDlk1expression is mediated by mTORC1; neuronalmTorcKO andRaptorcKO and pharmacological inhibition of mTORC1 recapitulate elevated neuronalDlk1expression. 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 ofDlk1in transgenic mice reduces the formation of mature oligodendrocytes and myelination. This study identifiesDlk1as an inhibitor of oligodendrocyte myelination and a mechanism linking altered neuronal signaling with oligodendrocyte dysfunction.