Transcription factor Zfp276 drives oligodendroglial differentiation and myelination by switching off the progenitor cell program.
Transcription factor Zfp276 drives oligodendroglial differentiation and myelination by switching off the progenitor cell program.
复制标题
DOI：
10.1093/nar/gkac042
复制
发表时间：
2022-02-28
影响因子：
14.9
通讯作者：
Küspert M
中科院分区：
文献类型：
--
作者：
Aberle T;Piefke S;Hillgärtner S;Tamm ER;Wegner M;Küspert M
在脊椎动物中枢神经系统的少突胶质细胞中，需要复杂的转录调节因子网络来确保神经元轴突的正确和及时的髓鞘形成。在这里，我们确定Zfp276，唯一的哺乳动物ZAD结构域含有锌指蛋白，作为少突胶质细胞分化和中央髓鞘下游的Sox10的转录调节因子。在中枢神经系统中，Zfp276仅在成熟的少突胶质细胞中表达。Zfp276的少突胶质细胞缺失导致出生后早期小鼠脊髓中髓鞘基因的表达强烈减少。Zfp276在培养的少突胶质前体细胞中的逆转录病毒过表达诱导成熟标记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功能性相互作用，使少突胶质细胞快速过渡到髓鞘形成阶段。所提出的Zfp 276在OL中的促分化机制的图示。OPCs可以向成熟OL分化，或者在存在不成熟因子和髓鞘形成抑制剂的情况下维持在OPC状态。在分化时，OL诱导髓鞘形成相关基因以促进神经元轴突的适当髓鞘形成。与OPC维持相关的基因和与终末分化相关的基因都受到Sox10的正调控。Zfp276与Zeb2协同作用，能够通过转录抑制OPC相关基因的基因调控区来拮抗其Sox10依赖性激活，从而将规模转向OL分化和髓鞘形成。
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. Graphical representation of the proposed pro-differentiating mechanism of Zfp276 in OLs. OPCs can differentiate toward mature OLs or are maintained in the OPC state in the presence of immaturity factors and inhibitors of myelination. Upon differentiation, OLs induce myelination-associated genes to facilitate proper myelination of neuronal axons. Both the genes related to OPC maintenance and those related to terminal differentiation are positively regulated by Sox10. Zfp276, in concert with Zeb2, is able to antagonize the Sox10-dependent activation of OPC-related genes by transcriptional repression of their gene regulatory regions, thereby shifting the scale toward OL differentiation and myelination.
登录
查看更多内容
DOI：
10.1083/jcb.200912142
发表时间：
2010-05-17
期刊：
The Journal of cell biology
影响因子：
--
作者：
Finzsch M;Schreiner S;Kichko T;Reeh P;Tamm ER;Bösl MR;Meijer D;Wegner M
通讯作者：
Wegner M
影响因子：
5.3
作者：
Kuhlbrodt, K;Herbarth, B;Wegner, M
通讯作者：
Wegner, M
影响因子：
4.5
作者：
Hornig J;Fröb F;Vogl MR;Hermans-Borgmeyer I;Tamm ER;Wegner M
通讯作者：
Wegner M
DOI：
10.1242/dev.098418
发表时间：
2014-01
期刊：
Development (Cambridge, England)
影响因子：
--
作者：
Hoffmann SA;Hos D;Küspert M;Lang RA;Lovell-Badge R;Wegner M;Reiprich S
通讯作者：
Reiprich S
影响因子：
--
作者：
Jones, Erin A.;Jang, Sung-Wook;Svaren, John
通讯作者：
Svaren, John