State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China; Cancer Research Center of Xiamen University, Xiamen, Fujian 361102, China.
School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian 361102, China; XMU School of Pharmaceutical Sciences-Amogene Joint R&D Center for Genetic Diagnostics, Amogene Biotech, Xiamen, Fujian 361102, China; The First Affiliated Hospital, Medical College, Xiamen University, Xiamen, Fujian 361102, China.
Neuron. 2019 May 8;102(3):587-601.e7. doi: 10.1016/j.neuron.2019.02.018. Epub 2019 Mar 12.
Nucleoporins (Nups) are involved in neural development, and alterations in Nup genes are linked to human neurological diseases. However, physiological functions of specific Nups and the underlying mechanisms involved in these processes remain elusive. Here, we show that tissue-specific depletion of the nucleoporin Seh1 causes dramatic myelination defects in the CNS. Although proliferation is not altered in Seh1-deficient oligodendrocyte progenitor cells (OPCs), they fail to differentiate into mature oligodendrocytes, which impairs myelin production and remyelination after demyelinating injury. Genome-wide analyses show that Seh1 regulates a core myelinogenic regulatory network and establishes an accessible chromatin landscape. Mechanistically, Seh1 regulates OPCs differentiation by assembling Olig2 and Brd7 into a transcription complex at nuclear periphery. Together, our results reveal that Seh1 is required for oligodendrocyte differentiation and myelination by promoting assembly of an Olig2-dependent transcription complex and define a nucleoporin as a key player in the CNS.
核孔蛋白（Nups）参与神经发育，Nup 基因的改变与人类神经疾病有关。然而，特定 Nups 的生理功能以及这些过程涉及的潜在机制仍不清楚。在这里，我们表明，核孔蛋白 Seh1 的组织特异性缺失会导致中枢神经系统（CNS）中髓鞘形成的严重缺陷。尽管 Seh1 缺陷性少突胶质前体细胞（OPC）的增殖没有改变，但它们不能分化为成熟的少突胶质细胞，这会损害脱髓鞘损伤后的髓鞘形成和髓鞘再生。全基因组分析表明，Seh1 调节核心髓鞘生成调节网络，并建立可及的染色质景观。在机制上，Seh1 通过将 Olig2 和 Brd7 组装到核周的转录复合物中，调节 OPCs 的分化。总之，我们的结果表明，Seh1 通过促进依赖 Olig2 的转录复合物的组装来促进少突胶质细胞分化和髓鞘形成，从而对少突胶质细胞分化和髓鞘形成是必需的，并将核孔蛋白定义为 CNS 中的关键参与者。
