State Key Laboratory of Ophthalmology, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, 510060, China.
Institute for Metabolic and Neuropsychiatric Disorders, Binzhou Medical University Hospital, Binzhou, China.
Mol Neurobiol. 2019 Mar;56(3):1719-1736. doi: 10.1007/s12035-018-1186-6. Epub 2018 Jun 19.
Mutations in the human transcription factor gene ZEB2 cause Mowat-Wilson syndrome, a congenital disorder characterized by multiple and variable anomalies including microcephaly, Hirschsprung disease, intellectual disability, epilepsy, microphthalmia, retinal coloboma, and/or optic nerve hypoplasia. Zeb2 in mice is involved in patterning neural and lens epithelia, neural tube closure, as well as in the specification, differentiation and migration of neural crest cells and cortical neurons. At present, it is still unclear how Zeb2 mutations cause retinal coloboma, whether Zeb2 inactivation results in retinal degeneration, and whether Zeb2 is sufficient to promote the differentiation of different retinal cell types. Here, we show that during mouse retinal development, Zeb2 is expressed transiently in early retinal progenitors and in all non-photoreceptor cell types including bipolar, amacrine, horizontal, ganglion, and Müller glial cells. Its retina-specific ablation causes severe loss of all non-photoreceptor cell types, cell fate switch to photoreceptors by retinal progenitors, and elevated apoptosis, which lead to age-dependent retinal degeneration, optic nerve hypoplasia, synaptic connection defects, and impaired ERG (electroretinogram) responses. Moreover, overexpression of Zeb2 is sufficient to promote the fate of all non-photoreceptor cell types at the expense of photoreceptors. Together, our data not only suggest that Zeb2 is both necessary and sufficient for the differentiation of non-photoreceptor cell types while simultaneously inhibiting the photoreceptor cell fate by repressing transcription factor genes involved in photoreceptor specification and differentiation, but also reveal a necessity of Zeb2 in the long-term maintenance of retinal cell types. This work helps to decipher the etiology of retinal atrophy associated with Mowat-Wilson syndrome and hence will impact on clinical diagnosis and management of the patients suffering from this syndrome.
人类转录因子基因 ZEB2 的突变导致 Mowat-Wilson 综合征，这是一种先天性疾病，其特征是多种和可变的异常，包括小头畸形、先天性巨结肠、智力障碍、癫痫、小眼症、视网膜裂孔和/或视神经发育不良。小鼠中的 Zeb2 参与神经和晶状体上皮的模式形成、神经管闭合以及神经嵴细胞和皮质神经元的特化、分化和迁移。目前，尚不清楚 Zeb2 突变如何导致视网膜裂孔，Zeb2 失活是否导致视网膜变性，以及 Zeb2 是否足以促进不同视网膜细胞类型的分化。在这里，我们显示在小鼠视网膜发育过程中，Zeb2 早期在视网膜祖细胞中短暂表达，并在所有非光感受器细胞类型中表达，包括双极、无长突、水平、节细胞和 Müller 胶质细胞。其视网膜特异性缺失导致所有非光感受器细胞类型严重丢失，视网膜祖细胞向光感受器的细胞命运转变，以及凋亡增加，导致年龄依赖性视网膜变性、视神经发育不良、突触连接缺陷和 ERG（视网膜电图）反应受损。此外，Zeb2 的过表达足以促进所有非光感受器细胞类型的命运，而牺牲光感受器。总之，我们的数据不仅表明 Zeb2 对于非光感受器细胞类型的分化是必要和充分的，同时通过抑制涉及光感受器特化和分化的转录因子基因来抑制光感受器细胞命运，而且还揭示了 Zeb2 在维持视网膜细胞类型的长期稳定性中的必要性。这项工作有助于解析与 Mowat-Wilson 综合征相关的视网膜萎缩的病因，从而影响该综合征患者的临床诊断和管理。
