Lens induction is a classical developmental model allowing investigation of cell specification, spatiotemporal control of gene expression, as well as how transcription factors are integrated into highly complex gene regulatory networks (GRNs). Pax6 represents a key node in the gene regulatory network governing mammalian lens induction. Meis1 and Meis2 homeoproteins are considered as essential upstream regulators of Pax6 during lens morphogenesis based on their interaction with the ectoderm enhancer (EE) located upstream of Pax6 transcription start site. Despite this generally accepted regulatory pathway, Meis1-, Meis2- and EE-deficient mice have surprisingly mild eye phenotypes at placodal stage of lens development. Here, we show that simultaneous deletion of Meis1 and Meis2 in presumptive lens ectoderm results in arrested lens development in the pre-placodal stage, and neither lens placode nor lens is formed. We found that in the presumptive lens ectoderm of Meis1/Meis2 deficient embryos Pax6 expression is absent. We demonstrate using chromatin immunoprecipitation (ChIP) that in addition to EE, Meis homeoproteins bind to a remote, ultraconserved SIMO enhancer of Pax6. We further show, using in vivo gene reporter analyses, that the lens-specific activity of SIMO enhancer is dependent on the presence of three Meis binding sites, phylogenetically conserved from man to zebrafish. Genetic ablation of EE and SIMO enhancers demostrates their requirement for lens induction and uncovers an apparent redundancy at early stages of lens development. These findings identify a genetic requirement for Meis1 and Meis2 during the early steps of mammalian eye development. Moreover, they reveal an apparent robustness in the gene regulatory mechanism whereby two independent "shadow enhancers" maintain critical levels of a dosage-sensitive gene, Pax6, during lens induction.

• MeSH
• Zebrafish genetics   MeSH
• Ectoderm growth & development   pathology   MeSH
• Gene Regulatory Networks genetics   MeSH
• Homeodomain Proteins genetics   metabolism   MeSH
• Humans MeSH
• Mice MeSH
• Neoplasm Proteins genetics   metabolism   MeSH
• Eye growth & development   metabolism   pathology   MeSH
• Lens, Crystalline growth & development   metabolism   pathology   MeSH
• Myeloid Ecotropic Viral Integration Site 1 Protein MeSH
• PAX6 Transcription Factor genetics   metabolism   MeSH
• Binding Sites MeSH
• Gene Expression Regulation, Developmental MeSH
• Enhancer Elements, Genetic genetics   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Homeodomain Proteins MeSH
• MEIS1 protein, human MeSH Browser
• Meis1 protein, mouse MeSH Browser
• Mrg1 protein, mouse MeSH Browser
• Neoplasm Proteins MeSH
• Pax6 protein, mouse MeSH Browser
• Myeloid Ecotropic Viral Integration Site 1 Protein MeSH
• PAX6 Transcription Factor MeSH

The vertebrate eye is a highly specialized sensory organ, which is derived from the anterior neural plate, head surface ectoderm, and neural crest-derived mesenchyme. The single central eye field, generated from the anterior neural plate, divides to give rise to the optic vesicle, which evaginates toward the head surface ectoderm. Subsequently, the surface ectoderm, in conjunction with the optic vesicle invaginates to form the lens vesicle and double-layered optic cup, respectively. This complex process is controlled by transcription factors and several intracellular and extracellular signaling pathways including WNT/β-catenin signaling. This signaling pathway plays an essential role in multiple developmental processes and has a profound effect on cell proliferation and cell fate determination. During eye development, the activity of WNT/β-catenin signaling is tightly controlled. Faulty regulation of WNT/β-catenin signaling results in multiple ocular malformations due to defects in the process of cell fate determination and differentiation. This mini-review summarizes recent findings on the role of WNT/β-catenin signaling in eye development. Whilst this mini-review focuses on loss-of-function and gain-of-function mutants of WNT/β-catenin signaling components, it also highlights some important aspects of β-catenin-independent WNT signaling in the eye development at later stages.

• Keywords
• WNT, development, differentiation, retina, β-catenin,
• Publication type
• Journal Article MeSH
• Review MeSH

The Wnt/β-catenin signaling pathway controls many processes during development, including cell proliferation, cell differentiation and tissue homeostasis, and its aberrant regulation has been linked to various pathologies. In this study we investigated the effect of ectopic activation of Wnt/β-catenin signaling during lens fiber cell differentiation. To activate Wnt/β-catenin signaling in lens fiber cells, the transgenic mouse referred to as αA-CLEF was generated, in which the transactivation domain of β-catenin was fused to the DNA-binding protein LEF1, and expression of the transgene was controlled by αA-crystallin promoter. Constitutive activation of Wnt/β-catenin signaling in lens fiber cells of αA-CLEF mice resulted in abnormal and delayed fiber cell differentiation. Moreover, adult αA-CLEF mice developed cataract, microphthalmia and manifested downregulated levels of γ-crystallins in lenses. We provide evidence of aberrant expression of cell cycle regulators in embryonic lenses of αA-CLEF transgenic mice resulting in the delay in cell cycle exit and in the shift of fiber cell differentiation to the central fiber cell compartment. Our results indicate that precise regulation of the Wnt/β-catenin signaling activity during later stages of lens development is essential for proper lens fiber cell differentiation and lens transparency.

• MeSH
• beta Catenin genetics   metabolism   MeSH
• Cell Differentiation genetics   MeSH
• Cell Cycle genetics   MeSH
• DNA-Binding Proteins genetics   metabolism   MeSH
• Epithelial Cells metabolism   MeSH
• Cataract genetics   metabolism   MeSH
• Crystallins genetics   metabolism   MeSH
• Humans MeSH
• Microphthalmos genetics   metabolism   MeSH
• Mice, Inbred C57BL MeSH
• Mice, Transgenic genetics   metabolism   MeSH
• Mice MeSH
• Lens, Crystalline metabolism   MeSH
• Promoter Regions, Genetic genetics   MeSH
• Wnt Signaling Pathway genetics   MeSH
• Signal Transduction genetics   MeSH
• Lymphoid Enhancer-Binding Factor 1 MeSH
• Gene Expression Regulation, Developmental MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• beta Catenin MeSH
• DNA-Binding Proteins MeSH
• Crystallins MeSH
• Lef1 protein, mouse MeSH Browser
• Lymphoid Enhancer-Binding Factor 1 MeSH