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Development. 2015 Oct 1;142(19):3383-93. doi: 10.1242/dev.125393.

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

Author information

1
Edith J. Crawley Vision Research Center, Department of Ophthalmology, University of Cincinnati School of Medicine, Cincinnati, OH 45267, USA School of Optometry, Indiana University, Bloomington, IN 47405, USA zhang512@iu.edu liuchia@iu.edu.
2
Department of Ophthalmology, Chang-Gung Memorial Hospital, Linkou, Taoyuan 333, Taiwan, R.O.C Chang-Gung University College of Medicine, Taoyuan 33302, Taiwan, R.O.C.
3
Edith J. Crawley Vision Research Center, Department of Ophthalmology, University of Cincinnati School of Medicine, Cincinnati, OH 45267, USA Undergraduate Programs of Biology, Ohio State University, Columbus, OH 43210, USA.
4
Edith J. Crawley Vision Research Center, Department of Ophthalmology, University of Cincinnati School of Medicine, Cincinnati, OH 45267, USA.
5
Health Research Institute, National Institute of Advanced Industrial Science and Technology, Takamatsu 761-0395, Japan.

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 (Ctnnb1(cKO)) or co-receptors Lrp5/6 (Lrp5/6(cKO)) in corneal stromal cells results in precocious stratification of the corneal epithelium. By contrast, ectopic expression of a murine Ctnnb1 gain-of-function mutant (Ctnnb1(cGOF)) 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 Ctnnb1(cKO). Conditional ablation of Bmp4 eradicates the phenotype produced in Ctnnb1(cKO) 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.

KEYWORDS:

Bmp4; Mesenchymal-epithelial interactions; Mouse; Ocular surface; Precocious epithelium stratification; Wnt/β-catenin signaling

PMID:
26443636
PMCID:
PMC4631757
DOI:
10.1242/dev.125393
[Indexed for MEDLINE]
Free PMC Article

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