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Chia-Yang Liu, Gracia Ng, Lung-Kun Yeh, Hongshan Liu, Yujin Zhang, Winston Kao; Role of Shp2 Protein Phosphatase in Mouse Corneal Epithelium Stratification. Invest. Ophthalmol. Vis. Sci. 2013;54(15):4718.
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© ARVO (1962-2015); The Authors (2016-present)
Proper stratification is essential for the homeostasis of stratified epithelia. The cellular and molecular mechanisms by which this process is initiated and maintained have not been clearly identified. Present study aims at elucidating the roles of Shp2 on surface epithelium stratification.
Shp2 was ablated in stratified epithelia of triple transgenic Krt14-rtTA/tet-O-Cre/Shp2f/f mice fed with doxycycline (Dox) chow at different embryonic and postnatal ages. In another series of experiment, epithelial debridement was performed in adult mice. Excised mouse eyes from experimental mice were subjected to histology and immunohistochemistry examination.
When Dox induction began prior to eyelid closure, the neonates of Shp2 mutant dies within 24 hours after birth with eyelid open. When Dox was given after E16.5, Shp2 mutants were born with normal eyelid development but the mutant died shortly after P21. Corneal epithelium anomaly was prominent in that it only consisted of 1-2 layers in comparison to 5-6 cell layers seen in heterozygote littermate. Interestingly, the morphology of skin, conjunctiva and lacrimal and Meibomian glands appeared un-affected. Cessation of Dox induction at P21 allowed the mutant mice live to adulthood and corneal epithelium resumed 5-6 cell layers. Similarly, corneal epithelium was reduced to 1-2 cell layers in mutant mice fed Dox from P21 to P42. Furthermore, the re-stratification during wound healing was compromised when corneal epithelial debridement was generated in the adult Shp2 mutant mice. We found that loss of Shp2 from corneal epithelium caused significant decrease in cell proliferation but no effect on apoptosis or corneal-type differentiation. Strikingly, the numbers of desmosome and hemidesmosome dramatically reduced in Shp2 mutant corneas. Immunostaining revealed that laminin-b1 and E-cadherin were down-regulated in Shp2 mutant corneas as compared to those of control mice. Noted that the cellular and molecular deficiencies concerning corneal epithelial stratification are reversible upon Dox induction is ceased, suggesting that epithelial progenitor (stem) cells are not affected in corneas of Shp2 mutant mice.
Our data suggest that Shp2’s role in sustaining cell proliferation and strengthening a tissue’s foundation is essential for proper epithelial stratification during corneal morphogenesis and homeostasis.
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