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Yuka Okada, Lingling Zhang, Yujin Zhang, Yen-Chiao Wang, Shizuya Saika, Chia-Yang Liu; Shp2 protein tyrosine phosphatase affects the interplay between corneal epithelium and nerve fibers. Invest. Ophthalmol. Vis. Sci. 2018;59(9):2266.
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© ARVO (1962-2015); The Authors (2016-present)
Corneal nerves are important for the corneal homeostasis and for protection against corneal injury. We presented that Shp2cKO mouse strain is potential models to study the role of epithelium-nerve interaction and also a novel animal models for neurotrophic keratopathy (ARVO 2017). Therefore, we explored the mechanisms and treatment of this mouse.
1) To understand the molecular mechanism by which Shp2-mediated MAPK signaling pathway plays a pivotal role in trigeminal innervation, we transfected TKE2 cells with small interfering RNA (siRNA) against Shp2, Mek1/2 and Akt1/2, respectively, and then co-cultured with primary trigeminal ganglion cells (TGCs) isolated from C57BL/6 mice at P10. The TGC neurites were allowed to grow in co-culture for 72 hours, then the neurite fiber lengths were measured and analyzed quantitatively. 2) Shp2 was conditionally knocked-out (Shp2cko) in the corneal epithelium administrated with doxycycline (Dox) from postnatal day 21 (P21) to P110. qPCR analyzed Shp2, ΔNp63 and nerve growth factor (NGF) gene expression levels of the corneal epithelium. 3) Further, the mice were divided into three groups (control, Shp2ckocontrol, Shp2cko NGF) NGF eye drop (200μg/ml) was applied 2 times daily for 8 weeks.
1) TGC neurite outgrowth was significantly retarded by siRNA-mediated knockdown of Shp2 and Mek1/2 but not by Akt1/2. 2) We found that ΔNp63 and NGF gene expression were downregulated in Shp2cko, as compared with those in Shp2WT littermates. 3) NGF eye drop improve the corneal epithelial stratification, corneal sensation and nerve innervation.
The overall objective of this proposal is to elucidate the role of Shp2→Mek→ΔNp63 signaling axis in CE stratification and corneal innervation during mouse corneal development and homeostasis. NGF therapy may represent a novel approach to animal models for neurotrophic keratopathy.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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