14-3-3σ Controls Corneal Epithelium Homeostasis and Wound Healing

The corneal epithelium protects the eye from environmental injury. Cornea-related diseases are the second major cause of blindness after cataract. Loss of vision occurs primarily from corneal scarring and vascularization.1 Vitamin A deficiency causes xerophthalmia, which is still a leading cause of childhood blindness due to corneal opacity associated with neovascularization. Because the corneal epithelium completely turns over every 7 to 10 days, there is ongoing corneal epithelial differentiation from proliferative progenitor cells scattered throughout the corneal epithelium and from the stem cells concentrated in the limbal region.2–4 Progenitor cells in the basal layer divide and migrate gradually to the upper epithelial layer. During this process, the cells switch expression of cytokeratins from the progenitor markers keratin-5 (K5) and -14 (K14) to the differentiation-specific isoforms keratin-3 (K3) and -12 (K12).5 The differentiated cells in the superficial layer then form tight junctions, which function as a barrier to protect the cornea.6,7 After injury, the corneal epithelium is rapidly repopulated via a wound-healing process involving mobilization of the corneal stem cells. This wound-healing process is composed of three sequential and partially overlapping steps including cell migration, proliferation, and differentiation.8,9 14-3-3σ is essential for skin epithelial differentiation,10,11 as demonstrated by the studies on the repeated epilation (Er) mouse that carries a null mutation in 14-3-3σ. 14-3-3σ is unique among seven 14-3-3 isoforms, which act exclusively as homodimers and are able to suppress tumor formation, and its expression is restricted to stratified squamous epithelial cells. It is induced at the transition from basal progenitor cells to suprabasal cells during the epidermal keratinocyte differentiation.10,12 14-3-3σ expression has been confined to corneal and conjunctival epithelial cells in humans and is secreted into the culture medium from either primary cells or cell lines.13 In this report, we show that mice mutant for both copies of 14-3-3σ are defective in embryonic corneal development. Although the heterozygous mice exhibit normal corneal development and epithelial homeostasis during embryonic and early postnatal development, they develop an age-dependent corneal plaque formation associated with corneal epithelial wound-healing dysfunction and meibomian gland atrophy.