| First Author | Zhang Y | Year | 2015 |
| Journal | Development | Volume | 142 |
| Issue | 19 | Pages | 3383-93 |
| PubMed ID | 26443636 | Mgi Jnum | J:225349 |
| Mgi Id | MGI:5693171 | Doi | 10.1242/dev.125393 |
| Citation | Zhang Y, et al. (2015) Wnt/beta-catenin signaling modulates corneal epithelium stratification via inhibition of Bmp4 during mouse development. Development 142(19):3383-93 |
| abstractText | 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. |
