Institut für Biochemie, Friedrich-Alexander-Universität Erlangen-Nürnberg, D-91054, Erlangen, Germany.
Institut für Humananatomie und Embryologie, Universität Regensburg, D-93053, Regensburg, Germany.
Nucleic Acids Res. 2022 Feb 28;50(4):1951-1968. doi: 10.1093/nar/gkac042.
In oligodendrocytes of the vertebrate central nervous system a complex network of transcriptional regulators is required to ensure correct and timely myelination of neuronal axons. Here we identify Zfp276, the only mammalian ZAD-domain containing zinc finger protein, as a transcriptional regulator of oligodendrocyte differentiation and central myelination downstream of Sox10. In the central nervous system, Zfp276 is exclusively expressed in mature oligodendrocytes. Oligodendroglial deletion of Zfp276 led to strongly reduced expression of myelin genes in the early postnatal mouse spinal cord. Retroviral overexpression of Zfp276 in cultured oligodendrocyte precursor cells induced precocious expression of maturation markers and myelin genes, further supporting its role in oligodendroglial differentiation. On the molecular level, Zfp276 directly binds to and represses Sox10-dependent gene regulatory regions of immaturity factors and functionally interacts with the transcriptional repressor Zeb2 to enable fast transition of oligodendrocytes to the myelinating stage.
在脊椎动物中枢神经系统的少突胶质细胞中，需要一个复杂的转录调控网络来确保神经元轴突的正确和及时髓鞘化。在这里，我们鉴定出 Zfp276，即唯一的哺乳动物 ZAD 结构域含有锌指蛋白，作为 Sox10 下游少突胶质细胞分化和中枢髓鞘形成的转录调节剂。在中枢神经系统中，Zfp276 仅在成熟的少突胶质细胞中表达。少突胶质细胞中 Zfp276 的缺失导致新生小鼠脊髓中髓鞘基因的表达明显减少。逆转录病毒过表达 Zfp276 在培养的少突胶质前体细胞中诱导成熟标志物和髓鞘基因的早熟表达，进一步支持其在少突胶质细胞分化中的作用。在分子水平上，Zfp276 直接结合并抑制不成熟因子的 Sox10 依赖性基因调控区，并与转录抑制因子 Zeb2 相互作用，使少突胶质细胞快速过渡到髓鞘形成阶段。
