Key Laboratory of Birth Defects and Related Diseases of Women and Children of Ministry of Education, Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu 610041, China.
Department of Pediatrics, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio 45229.
J Neurosci. 2018 Feb 7;38(6):1575-1587. doi: 10.1523/JNEUROSCI.2674-17.2018. Epub 2018 Jan 11.
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 in cerebellar radial glia exhibit severe deficits in Bergmann glia specification, and develop cerebellar cortical lamination dysgenesis and locomotion defects. In developing -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, ablation in granule neuron precursors or oligodendrocyte progenitors does not affect Bergmann glia formation, despite myelination deficits caused by 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. 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 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 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.
Bergmann 胶质细胞在发育过程中促进颗粒神经元迁移，并维持小脑的组织和功能完整性。目前，小脑放射状胶质细胞向 Bergmann 胶质细胞分化的分子调控机制尚不完全清楚。在本报告中，我们发现 ZEB2（也称为 SIP1 或 ZFHX1B），一种 Mowat-Wilson 综合征相关转录调节因子，在 Bergmann 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失的小鼠表现出 Bergmann 胶质细胞分化严重缺陷，并出现小脑皮层层状结构发育不良和运动缺陷。在发育中的突变小脑中，颗粒神经元前体细胞的向内迁移受损，神经前体细胞的增殖减少，放射状胶质细胞不能分化为浦肯野细胞层中的 Bergmann 胶质细胞。相比之下，颗粒神经元前体细胞或少突胶质细胞前体细胞中的缺失并不影响 Bergmann 胶质细胞的形成，尽管在少突胶质细胞谱系中发生突变会导致髓鞘缺陷。转录组谱分析表明，ZEB2 调控一组 Bergmann 胶质细胞相关基因以及 FGF、NOTCH 和 TGFβ/BMP 信号通路成分。我们的数据表明，ZEB2 作为 Bergmann 胶质细胞形成的整体调节因子，确保小脑完整性的维持，这表明 Mowat-Wilson 综合征中 Bergmann 胶质发生功能障碍可能导致运动缺陷。Bergmann 胶质细胞对小脑的正常组织和功能回路至关重要，但控制 Bergmann 胶质细胞特化的分子机制仍不清楚。在这里，我们发现转录因子 ZEB2 在成熟的 Bergmann 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中缺失，但少突胶质细胞前体细胞或颗粒神经元前体细胞中缺失的小鼠，Bergmann 胶质细胞形成严重缺陷。在突变体中，没有建立起 Bergmann 胶质纤维形成的有序放射状支架，这对小脑层状结构至关重要，导致运动行为缺陷。这一发现表明 ZEB2 在 Bergmann 胶质细胞特化中具有先前未被认识的关键作用，并指出 ZEB2 功能障碍对 Mowat-Wilson 综合征中小脑运动障碍的重要贡献。
