Requirement of the Mowat-Wilson Syndrome Gene Zeb2 in the Differentiation and Maintenance of Non-photoreceptor Cell Types During Retinal Development.

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.