Shp2-mediated MAPK pathway regulates ΔNp63 in epithelium to promote corneal innervation and homeostasis

Yuka Okada, Yujin Zhang, Lingling Zhang, Lung Kun Yeh, Yen Chiao Wang, Shizuya Saika, Chia Yang Liu

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


Corneal nerve fibers serving sensory, reflex, and neurotrophic functions sustain corneal homeostasis and transparency to promote normal visual function. It is not known whether corneal epithelium is also important for the corneal innervation. Herein, we generated a compound transgenic mouse strain, K14rtTA;tetO-Cre (TC);Shp2flox/flox, in which Shp2 was conditionally knocked out from K14-positive cells including corneal epithelium (Shp2K14ce-cko) upon doxycycline (dox) administration. Our data reveal that Shp2K14ce-cko caused corneal denervation. More specifically, corneal epithelium thickness and corneal sensitivity reduced dramatically in Shp2K14ce-cko mice. In addition, corneal epithelial wound healing after debridement was delayed substantially in the mutant mice. These defects manifested in Shp2K14ce-cko mice resemble the symptoms of human neurotrophic keratopathy. Our in vitro study shows that neurite outgrowth of the mouse primary trigeminal ganglion cells (TGCs) was inhibited when as cocultured with mouse corneal epithelial cells (TKE2) transfected by Shp2-, Mek1/2-, or ∆Np63-targeted siRNA but not by Akt1/2-targeted siRNA. Furthermore, ∆Np63 RNA interference downregulated Ngf expression in TKE2 cells. Cotransfection experiments reveal that Shp2 tightly monitored ΔNp63 protein levels in HEK293 and TKE2 cells. Taken together, our data suggest that the Shp2-mediated MAPK pathway regulated ΔNp63, which in turn positively regulated Ngf in epithelium to promote corneal innervation and epithelial homeostasis.

Original languageEnglish (US)
Pages (from-to)630-642
Number of pages13
JournalLaboratory Investigation
Issue number4
StatePublished - Apr 1 2020
Externally publishedYes

Bibliographical note

Funding Information:
Acknowledgements Supported in part by grants from NIH/NEI EY29071 (CYL); Ministry of Science and Technology (MOST) grant (Taiwan) 1042314B182A097MY3 (LKY); and Chang Gung Medical Research Project grants: CMRPG3E1522 (LKY); CMRPG3H1381 (LKY). We thank Hui-Chun Kung and Ya-Ling Chen for preparation of TEM studies at the Microscope Center of Chang-Gung Memorial Hospital, Linko, Taiwan.

Publisher Copyright:
© 2019, The Author(s), under exclusive licence to United States and Canadian Academy of Pathology.


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