Dual-Mode Modulation of Smad Signaling by Smad-Interacting Protein Sip1 Is Required for Myelination in the Central Nervous System
Dual-Mode Modulation of Smad Signaling by Smad-Interacting Protein Sip1 Is Required for Myelination in the Central Nervous System
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DOI：
10.1016/j.neuron.2012.10.004
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发表时间：
2012-10
期刊：
影响因子：
16.2
通讯作者：
Qinjie Weng;Ying Chen;Haibo Wang;Xiaomei Xu;Bo Yang;Qiaojun He;W. Shou;Yan Chen;Y. Higashi-Y.-Hi
中科院分区：
文献类型：
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作者：
Qinjie Weng;Ying Chen;Haibo Wang;Xiaomei Xu;Bo Yang;Qiaojun He;W. Shou;Yan Chen;Y. Higashi-Y.-Hi
中枢神经系统（CNS）中少突胶质细胞的髓鞘形成对于大脑的正常功能至关重要，但控制这一过程的分子决定因素仍然知之甚少。碱性螺旋-环-螺旋转录因子 Olig1 和 Olig2 促进髓鞘形成，而骨形态发生蛋白 (BMP) 和 Wnt/β-连环蛋白信号传导抑制髓鞘形成。在这里，我们证明这些髓鞘形成的相反调节因子通过 Olig1/2 共同目标 Smad 相互作用蛋白 1 (Sip1) 在功能上相连。我们证明 Sip1 是中枢神经系统髓鞘形成的重要调节剂。 Sip1 通过拮抗 BMP 受体激活的 Smad 活性来抑制分化抑制信号，同时激活关键的少突胶质细胞促进因子。重要的是，Sip1 激活的关键靶点 Smad7 是少突胶质细胞分化所必需的，并且可以部分挽救因 Sip1 丢失而导致的分化缺陷。 Smad7 通过阻断 BMP 和 β-连环蛋白阴性调节途径来促进髓鞘形成。因此，我们的研究结果表明，Sip1介导的抑制信号传导拮抗作用对于促进中枢神经系统髓鞘形成至关重要，并指出了髓鞘修复的新介质。
Myelination by oligodendrocytes in the central nervous system (CNS) is essential for proper brain function, yet the molecular determinants that control this process remain poorly understood. The basic helix-loop-helix transcription factors Olig1 and Olig2 promote myelination, whereas bone morphogenetic protein (BMP) and Wnt/β-catenin signaling inhibit myelination. Here we show that these opposing regulators of myelination are functionally linked by the Olig1/2 common target Smad-interacting protein-1 (Sip1). We demonstrate that Sip1 is an essential modulator of CNS myelination. Sip1 represses differentiation inhibitory signals by antagonizing BMP receptor-activated Smad activity while activating crucial oligodendrocyte-promoting factors. Importantly, a key Sip1-activated target, Smad7, is required for oligodendrocyte differentiation and partially rescues differentiation defects caused by Sip1 loss. Smad7 promotes myelination by blocking the BMP- and β-catenin-negative regulatory pathways. Thus, our findings reveal that Sip1-mediated antagonism of inhibitory signaling is critical for promoting CNS myelination and point to new mediators for myelin repair.