The transcription factor Maz is essential for normal eye development.

Meade Haller,Marisol A. O'Neill,Olga Medina-Martinez,Dolores J. Lamb,Jill A. Rosenfeld,Milan Jamrich

doi:10.1242/dmm.044412

Meade Haller, Marisol A. O'Neill + Show 4 more

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https://doi.org/10.1242/dmm.044412

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Abstract

ABSTRACTWnt/β-catenin signaling has an essential role in eye development. Faulty regulation of this pathway results in ocular malformations, owing to defects in cell-fate determination and differentiation. Herein, we show that disruption of Maz, the gene encoding Myc-associated zinc-finger transcription factor, produces developmental eye defects in mice and humans. Expression of key genes involved in the Wnt cascade, Sfrp2, Wnt2b and Fzd4, was significantly increased in mice with targeted inactivation of Maz, resulting in abnormal peripheral eye formation with reduced proliferation of the progenitor cells in the region. Paradoxically, the Wnt reporter TCF-Lef1 displayed a significant downregulation in Maz-deficient eyes. Molecular analysis indicates that Maz is necessary for the activation of the Wnt/β-catenin pathway and participates in the network controlling ciliary margin patterning. Copy-number variations and single-nucleotide variants of MAZ were identified in humans that result in abnormal ocular development. The data support MAZ as a key contributor to the eye comorbidities associated with chromosome 16p11.2 copy-number variants and as a transcriptional regulator of ocular development.

Highlights

Formation of the eye is an evolutionarily conserved developmental process that leads to morphogenesis of the retina, lens, and associated eye structures
Expression of key genes involved in the Wnt cascade, Sfrp2, Wnt2b and Frizzled 4 (Fzd4) were significantly increased in mice with targeted inactivation of Maz, resulting in abnormal peripheral eye formation with reduced proliferation of the progenitor cells in the region
Molecular analysis indicates that Maz is necessary for the activation of the Wnt/ -catenin pathway and participates in the network controlling ciliary margin patterning

Summary

Introduction

Formation of the eye is an evolutionarily conserved developmental process that leads to morphogenesis of the retina, lens, and associated eye structures. Wnt pathway signaling is essential for multiple developmental events during embryogenesis regulating cell proliferation and fate decisions (Liu et al, 2007; Livesey and Cepko, 2001). It plays a fundamental role in human diseases (Wang et al, 2019). The activated Fzd/LRP complex transduces Wnt signaling into the cell through canonical and non-canonical signaling pathways. The canonical Wnt/ -catenin pathway acts through -catenin as a transcriptional cofactor, while the non-canonical pathway (Wnt/ planar cell polarity and Wnt/Ca2+ pathway) through FZD receptors and/or ROR1/ROR2/RYK co-receptors activates the PCP, RTK or Ca2+ signaling cascades (Katoh, 2017)

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