Genome-wide mapping of Olig2 targets in primary oligodendrocytes

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/ß-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 ß-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.中枢神经系统（central nervous system, CNS）内少突胶质细胞（oligodendrocytes）介导的髓鞘形成，对于大脑正常功能的维持至关重要，但调控该过程的分子决定因素仍未得到充分阐释。碱性螺旋-环-螺旋（basic helix-loop-helix）转录因子Olig1与Olig2可促进髓鞘形成，而骨形态发生蛋白（bone morphogenetic protein, BMP）及Wnt/β-连环蛋白（Wnt/ß-catenin）信号通路则会抑制髓鞘形成。本研究发现，这些功能相互拮抗的髓鞘形成调控因子，可通过Olig1/2的共同靶标Smad相互作用蛋白1（Smad-interacting protein-1, Sip1）实现功能关联。我们证实Sip1是中枢神经系统髓鞘形成的关键调控因子：其一方面通过拮抗BMP受体激活的Smad活性，抑制分化抑制信号；另一方面则激活少突胶质细胞生成所需的关键促进因子。尤为重要的是，Sip1激活的核心靶标Smad7对少突胶质细胞分化不可或缺，且可部分挽救Sip1缺失所导致的分化缺陷。Smad7通过阻断BMP与β-连环蛋白介导的负调控通路，促进髓鞘形成。综上，本研究揭示了Sip1介导的抑制信号拮抗作用在中枢神经系统髓鞘形成中的关键调控作用，并为髓鞘修复提供了全新的潜在靶点。