期刊
DEVELOPMENT
卷 142, 期 19, 页码 3383-3393出版社
COMPANY OF BIOLOGISTS LTD
DOI: 10.1242/dev.125393
关键词
Precocious epithelium stratification; Mesenchymal-epithelial interactions; Ocular surface; Wnt/beta-catenin signaling; Bmp4; Mouse
资金
- National Institutes of Health/National Eye Institute (NIH/NEI) [RO1 EY21501, EY13755]
- Research to Prevent Blindness
- Ohio Lions Foundation for Eye Research
- National Science Council Grants (Taiwan) [1012314B182A056MY3, 104-2314B182A097MY3]
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/beta-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 beta-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 beta-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 beta-catenin binds to and suppresses Bmp4 promoter activity. These data support the concept that cross-talk between the Wnt/beta-catenin/Bmp4 axis (in the stromal mesenchyme) and Bmp4/p63 signaling (in the epithelium) plays a pivotal role in epithelial stratification during corneal morphogenesis.
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