神经元通过Dlk1抑制少突胶质细胞分化的机制

神经元信号调控少突胶质细胞分化和髓鞘形成的机制并不清楚。少突胶质细胞分化和髓鞘形成障碍可以引发严重的脑疾病。我们首次发现，Rheb1/mTORC1活性下调会激活Dlk1的表达，进而抑制少突胶质细胞分化和髓鞘形成。Dlk1转录形成不同的剪接体，包括膜结合型mDLK1蛋白和分泌型sDLK1蛋白，后者可以分泌到细胞外，抑制多种细胞分化。本项目将解析神经元分泌的sDLK1在少突胶质细胞分化中的作用机制。前期结果支持科学假设：神经元分泌的sDLK1与少突胶质细胞膜上的mDLK1相互作用，启动下游信号通路，抑制了少突胶质细胞的分化。我们计划采用体外OPC分化体系、OPC中mDLK1被敲除并同时敲入sDLK1蛋白编码基因的转基因小鼠，和mDLK1-BioID2邻近蛋白标记技术，研究DLK1同型相互作用及相关的细胞内信号通路在少突胶质细胞分化中的调控机制。本项目的完成将为治疗病理性的髓鞘缺陷提供新思路。

How neuronal signals regulate OL differentiation and myelination is poorly understood. Suppressed differentiation of oligodendrocytes and hypomyelination can cause serious brain disease. Our previous study showed when neuronal Rheb/mTORC1 activity is impaired, it activates the expression of Dlk1, which we show is a novel inhibitor of oligodendrocyte formation and brain myelination. Dlk1 is a type I transmembrane protein but can be cleaved to release the ectodomain of the protein as a soluble factor to inhibit cell differentiation. This proposal examines how neuron-derived Dlk1 inhibits oligodendrocyte differentiation. We hypothesize that the sDLK1 (secretory DLK1 protein) secreted by neurons acted on oligodendrocyte precursor cells to initiate a signaling cascade that may involve membrane-anchored oligodendrocyte mDLK1 (membrane-bound DLK1 protein) as a co-receptor. Using OPC in vitro differentiation system, transgenic mice with sDLK1 encoded gene knock-in and endogenous Dlk1 knock-out, and mDLK1-BioD2 proximal protein labeling techniques, this proposal will examine the mechanism of neuronal control to oligodendrocyte differentiation by Dlk1. This study will enable the development of new molecular targets for the treatment of pathological myelin deficit.