ADAM17 transactivates EGFR signaling during embryonic eyelid closure. Invest Ophthalmol Vis Sci 2013 Jan 07;54(1):132-40
Date
12/06/2012Pubmed ID
23211830Pubmed Central ID
PMC3544417DOI
10.1167/iovs.12-11130Scopus ID
2-s2.0-84874531665 (requires institutional sign-in at Scopus site) 13 CitationsAbstract
PURPOSE: During mammalian embryonic eyelid closure ADAM17 has been proposed to play a role as a transactivator of epidermal growth factor receptor (EGFR) signaling by shedding membrane bound EGFR ligands. However, ADAM17 also sheds numerous other ligands, thus implicating ADAM17 in additional molecular pathways. The goal of this study was to experimentally establish the role of ADAM17 and determine ADAM17-mediated pathways essential for the embryonic eyelid closure.
METHODS: Wild-type (WT) and woe mice, carrying a hypomorphic mutation in Adam17, were evaluated using H&E and scanning electron microscopy. Expressions of ADAM17, EGFR, and the phosphorylated form EGFR-P were evaluated using immunohistochemistry. BrdU and TUNEL assays were used to evaluate cell proliferation and apoptosis, respectively. In vitro scratch assays of primary cultures were used to evaluate cell migration. Clinical and histologic analyses established if the hypermorphic Egfr(Dsk5) allele can rescue the woe embryonic eyelid closure.
RESULTS: woe mice exhibited a failure to develop the leading edge of the eyelid and consequently failure of the embryonic eyelid closure. Expression of ADAM17 was identified in the eyelid epithelium in the cells of the leading edge. ADAM17 is essential for epithelial cell migration, but does not play a role in proliferation and apoptosis. EGFR was expressed in both WT and woe eyelid epithelium, but the phosphorylated EGFR-P form was detected only in WT. The Egfr(Dsk5) allele rescued woe eyelid closure defects, but also rescued woe anterior segment defects and the absence of meibomian glands.
CONCLUSIONS: We provide in vivo genetic evidence that the role of ADAM17 during embryonic eyelid closure is to transactivate EGFR signaling.
Author List
Hassemer EL, Endres B, Toonen JA, Ronchetti A, Dubielzig R, Sidjanin DJAuthor
Danielle Sidjanin Maier PhD Nurse Practitioner in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
ADAM ProteinsADAM17 Protein
Animals
Cell Death
Cell Movement
Cell Proliferation
ErbB Receptors
Eyelids
Female
Gene Expression Regulation, Developmental
Genotype
Ligands
Male
Meibomian Glands
Mice
Mice, Inbred C57BL
Mice, Mutant Strains
Phenotype
Pregnancy
Primary Cell Culture
Signal Transduction
