Transcriptional Regulator ZEB2 Is Essential for Bergmann Glia Development
Transcriptional Regulator ZEB2 Is Essential for Bergmann Glia Development
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转录调节因子 ZEB2 对于伯格曼神经胶质细胞的发育至关重要
DOI：
10.1523/jneurosci.2674-17.2018
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发表时间：
2018-02-07
影响因子：
5.3
通讯作者：
Lu, Q. Richard
中科院分区：
文献类型：
--
作者：
He, Li;Yu, Kun;Lu, Q. Richard
伯格曼胶质细胞在发育过程中促进颗粒神经元迁移并维持小脑组织和功能完整性。目前，小脑放射状神经胶质细胞伯格曼神经胶质细胞规范的分子控制尚不完全清楚。在本报告中，我们表明ZEB2（又名SIP1或ZFHX1B）是一种莫瓦特-威尔逊综合征相关转录调节因子，在伯格曼神经胶质细胞中高度表达，但在小脑星形胶质细胞中几乎检测不到。小脑放射状胶质细胞中缺乏 Zeb2 的小鼠表现出伯格曼胶质细胞规范的严重缺陷，并出现小脑皮质层发育不全和运动缺陷。在发育中的 Zeb2 突变小脑中，颗粒神经元祖细胞的向内迁移受到损害，神经胶质前体的增殖减少，放射状神经胶质细胞无法分化为浦肯野细胞层中的伯格曼神经胶质细胞。相比之下，尽管少突胶质细胞谱系中的 Zeb2 突变导致髓鞘形成缺陷，但颗粒神经元前体或少突胶质细胞祖细胞中的 Zeb2 消融并不影响伯格曼胶质细胞的形成。转录组分析发现，ZEB2 调节一组伯格曼胶质细胞相关基因以及 FGF、NOTCH 和 TGFβ/BMP 信号通路组件。我们的数据显示，ZEB2 作为伯格曼胶质细胞形成的整体调节因子，确保维持小脑完整性，这表明伯格曼胶质细胞生成中的 ZEB2 功能障碍可能导致 Mowat-Wilson 综合征的运动缺陷。意义声明 伯格曼神经胶质细胞对于正常的小脑组织和功能电路至关重要，然而，控制伯格曼神经胶质细胞规格的分子机制仍然难以捉摸。在这里，我们发现转录因子ZEB2在成熟的伯格曼神经胶质细胞中高度表达，但在小脑星形胶质细胞中不表达。小脑放射状胶质细胞缺乏 Zeb2，但少突胶质细胞祖细胞或颗粒神经元祖细胞缺乏 Zeb2 的小鼠，在伯格曼胶质细胞形成中表现出严重缺陷。 Zeb2突变体中没有建立由对小脑层压至关重要的伯格曼胶质纤维形成的有序径向支架，表现出运动行为缺陷。这一发现证明了ZEB2在伯格曼神经胶质细胞规范中之前未被认识到的关键作用，并指出ZEB2功能障碍对Mowat-Wilson综合征小脑运动障碍的重要贡献。
Bergmann glia facilitate granule neuron migration during development and maintain the cerebellar organization and functional integrity. At present, molecular control of Bergmann glia specification from cerebellar radial glia is not fully understood. In this report, we show that ZEB2 (aka, SIP1 or ZFHX1B), a Mowat–Wilson syndrome-associated transcriptional regulator, is highly expressed in Bergmann glia, but hardly detectable in astrocytes in the cerebellum. The mice lacking Zeb2 in cerebellar radial glia exhibit severe deficits in Bergmann glia specification, and develop cerebellar cortical lamination dysgenesis and locomotion defects. In developing Zeb2-mutant cerebella, inward migration of granule neuron progenitors is compromised, the proliferation of glial precursors is reduced, and radial glia fail to differentiate into Bergmann glia in the Purkinje cell layer. In contrast, Zeb2 ablation in granule neuron precursors or oligodendrocyte progenitors does not affect Bergmann glia formation, despite myelination deficits caused by Zeb2 mutation in the oligodendrocyte lineage. Transcriptome profiling identified that ZEB2 regulates a set of Bergmann glia-related genes and FGF, NOTCH, and TGFβ/BMP signaling pathway components. Our data reveal that ZEB2 acts as an integral regulator of Bergmann glia formation ensuring maintenance of cerebellar integrity, suggesting that ZEB2 dysfunction in Bergmann gliogenesis might contribute to motor deficits in Mowat–Wilson syndrome. SIGNIFICANCE STATEMENT Bergmann glia are essential for proper cerebellar organization and functional circuitry, however, the molecular mechanisms that control the specification of Bergmann glia remain elusive. Here, we show that transcriptional factor ZEB2 is highly expressed in mature Bergmann glia, but not in cerebellar astrocytes. The mice lacking Zeb2 in cerebellar radial glia, but not oligodendrocyte progenitors or granular neuron progenitors, exhibit severe defects in Bergmann glia formation. The orderly radial scaffolding formed by Bergmann glial fibers critical for cerebellar lamination was not established in Zeb2 mutants, displaying motor behavior deficits. This finding demonstrates a previously unrecognized critical role for ZEB2 in Bergmann glia specification, and points to an important contribution of ZEB2 dysfunction to cerebellar motor disorders in Mowat–Wilson syndrome.