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Wnt/β-catenin signaling modulates corneal epithelium stratification via inhibition of Bmp4 during mouse development

Authors :
Mayu Yasunaga
Suohui Zhang
Yong Yuan
Chia-Yang Liu
Lung-Kun Yeh
Yujin Zhang
Winston W.-Y. Kao
Mindy K. Call
Source :
Development. 142:3383-3393
Publication Year :
2015
Publisher :
The Company of Biologists, 2015.

Abstract

The development of organs with an epithelial parenchyma relies on reciprocal mesenchymal-epithelial communication. Mouse corneal epithelium stratification is the consequence of a coordinated developmental process based on mesenchymal-epithelial interactions. The molecular mechanism underlying these interactions remains unclear. The Wnt/β-catenin signaling pathway is involved in fundamental aspects of development through the regulation of various growth factors. Here, we show that conditional ablation of either β-catenin (Ctnnb1cKO) or co-receptors Lrp5/6 (Lrp5/6cKO) in corneal stromal cells results in precocious stratification of the corneal epithelium. By contrast, ectopic expression of a murine Ctnnb1 gain-of-function mutant (Ctnnb1cGOF) retards corneal epithelium stratification. We also discovered that Bmp4 is upregulated in the absence of β-catenin in keratocytes, which further triggers ERK1/2 (Mapk3/1) and Smad1/5 phosphorylation and enhances transcription factor p63 (Trp63) expression in mouse corneal basal epithelial cells and in a human corneal epithelial cell line (HTCE). Interestingly, mouse neonates given a subconjunctival BMP4 injection displayed a phenotype resembling that of Ctnnb1cKO. Conditional ablation of Bmp4 eradicates the phenotype produced in Ctnnb1cKO mice. Furthermore, ChIP and promoter-luciferase assays show that β-catenin binds to and suppresses Bmp4 promoter activity. These data support the concept that cross-talk between the Wnt/β-catenin/Bmp4 axis (in the stromal mesenchyme) and Bmp4/p63 signaling (in the epithelium) plays a pivotal role in epithelial stratification during corneal morphogenesis.

Details

ISSN :
14779129 and 09501991
Volume :
142
Database :
OpenAIRE
Journal :
Development
Accession number :
edsair.doi.dedup.....351bc232c5c02df7a29904877d9c53bf