Abstract
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-2β (AP-2β) is highly expressed in the POM and important for anterior segment development. Using a mouse model in which AP-2β is conditionally deleted in the NCCs (AP-2β 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-2β 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-2β NCC KO mouse result from changes to regulatory signaling from the POM-derived stroma. Our findings suggest that stromal pathways such as Wnt/β-Catenin signaling may regulate BMP4 expression, which influences cell fate and stratification.
Highlights
The cornea is a highly specialized transparent tissue that constitutes the anterior surface of the eye
Zhang et al [38] found evidence that β-Catenin inhibits bone morphogenic protein 4 (BMP4) expression in the stroma prior to eyelid opening; after eyelid opening, Wnt/β-Catenin signaling is reduced, allowing for upregulation of BMP4 in the stroma [38], which promotes epithelial stratification through Smad-dependent activation of transcription factor P63 [45]. These findings focused on paracrine signaling from BMP4 produced in the stroma, the general expression pattern is in agreement with our observation of reduced stratification in the absence of BMP4 for the mutant corneal epithelium (Figure 7) and paralleled our findings of basal epithelial BMP4
Activating protein-2β (AP-2β) deletion in the neural crest cells (NCCs)-derived periocular mesenchyme (POM), as carried out in the AP-2β NCC KO model, was shown to indirectly elicit profound effects on corneal epithelial cell phenotype and stratification, the latter of which is of surface ectoderm origin
Summary
The cornea is a highly specialized transparent tissue that constitutes the anterior surface of the eye. The periocular mesenchyme (POM), which is formed predominantly from neural crest cells (NCCs) and to a lesser extent paraxial mesoderm cells, gives rise to the corneal endothelium and stroma [1,2,3]. POM migration occurs at embryonic day (E) 12.5 into the space between the lens and surface ectoderm (SE) [4]. Between E13.5 and 15.5, the POM cells closest to the lens condense into the endothelium, while the others become extracellular matrix (ECM)-secreting keratocytes forming the stroma [4]. The corneal epithelium forms from the anterior SE. It remains only 1–2 cell layers until stratification is initiated at the time of eyelid opening at post-embryonic day (P) 12 [4,5]
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