RESUMO
The cornea is an anterior eye structure specialized for vision. The corneal endothelium and stroma are derived from the periocular mesenchyme (POM), which originates from neural crest cells (NCCs), while the stratified corneal epithelium develops from the surface ectoderm. Activating protein-2ß (AP-2ß) is highly expressed in the POM and important for anterior segment development. Using a mouse model in which AP-2ß is conditionally deleted in the NCCs (AP-2ß NCC KO), we investigated resulting corneal epithelial abnormalities. Through PAS and IHC staining, we observed structural and phenotypic changes to the epithelium associated with AP-2ß deletion. In addition to failure of the mutant epithelium to stratify, we also observed that Keratin-12, a marker of the differentiated epithelium, was absent, and Keratin-15, a limbal and conjunctival marker, was expanded across the central epithelium. Transcription factors PAX6 and P63 were not observed to be differentially expressed between WT and mutant. However, growth factor BMP4 was suppressed in the mutant epithelium. Given the non-NCC origin of the epithelium, we hypothesize that the abnormalities in the AP-2ß NCC KO mouse result from changes to regulatory signaling from the POM-derived stroma. Our findings suggest that stromal pathways such as Wnt/ß-Catenin signaling may regulate BMP4 expression, which influences cell fate and stratification.
Assuntos
Proteína Morfogenética Óssea 4/metabolismo , Regulação para Baixo , Epitélio Corneano/anormalidades , Deleção de Genes , Fator de Transcrição AP-2/genética , Animais , Proteína Morfogenética Óssea 4/genética , Diferenciação Celular , Epitélio Corneano/metabolismo , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Técnicas de Inativação de Genes , Queratina-12/metabolismo , Queratina-15/metabolismo , Masculino , Camundongos , Crista Neural/metabolismo , Fenótipo , Fator de Transcrição AP-2/metabolismo , Via de Sinalização WntRESUMO
The cornea is a highly specialized transparent tissue located at the anterior most surface of the eye. It consists of three main layers, the outer stratified squamous epithelium, the inner endothelium, and the intermediate stroma. Formation of these layers during development involves a complex interaction between ectodermal-derived structures, such as the overlying head ectoderm with the periocular mesenchyme (POM), the latter of which is comprised of neural crest cells (NCC) and mesoderm-derived progenitor cells. Regulation of corneal epithelial development, including both epithelial cell fate and stratification, has been shown to depend on numerous bi-directional mesenchymal-epithelial signaling pathways. In this review we pay particular attention to the genes and signaling pathways that involve the POM.