Shp2 protein tyrosine phosphatase affects corneal epithelial stratification and innervation

Abstract

Purpose : Corneal nerves are important for the detection of noxious stimuli at the surface of the cornea and for protection against corneal injury. We examine whether genetically impaired corneal epithelial stratification due to Shp2 deficiency or over expression can impact corneal innervation during development and nerve integrity in mature cornea.

Methods : Shp2 was conditionally knocked-out (Shp2^cko) or ectopic expression of a murine gain-of-function mutant (Shp2^cGOF) in the corneal epithelium administrated with doxycycline (Dox) from postnatal day 21 (P21) to P35, P50, and P110, respectively. Mouse eyes were subjected to histology and immunohistochemistry. In corneal epithelial wound healing experiment of Shp2^cko, administrated with Dox from P60 to P74 were used. Time dependent closure of a 2.0 mm diameter central corneal epithelial debridement was monitored in the right eyes of mice for up to 48 h using fluorescein green staining.

Results : Shp2^cko mice, corneal epithelial cell layers are decreased. Whole-mount examination of nerve specific protein, anti-neuron-specific β-tubulin antibody (TUJ1) positive nerve was dramatically reduced in Shp2^cko mice as compare to control cornea. Conversely, corneal epithelial cell layers and TUJ1 positive nerve was increased in Shp2^cGOF. In corneal wound healing model, the corneal epithelial defect remaining was larger in Shp2^cko mice as compared with control mice.

Conclusions : These data argue that the corneal epithelial stratification is indispensable for corneal innervation. The Shp2^cKO and Shp2^cGOF mouse strains are potential models to study the role of epithelium-nerve interaction and also a novel animal models for neurotrophic keratopathy.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.