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D J Sidjanin, Joseph Toonen; Adisintegrin and metalloproteinase 10 (ADAM10) is a regulator of lens development. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):4007.
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© ARVO (1962-2015); The Authors (2016-present)
ADAM10 and ADAM17 are two closely related members of the disintegrin and metalloproteinase (ADAM) family with a role in ectodomain cleavage of membrane bound proteins. Both ADAM10 and ADAM17 have been implicated in proteolytic cleavage of EGRF ligands as well as NOTCH receptors. Our previous studies have shown that ADAM17 solely transactivates EGFR signaling. Therefore, we proceeded to evaluate the role of ADAM10 during lens development as a potential regulator of NOTCH signaling. To test this hypothesis, we set out to generate Adam10 conditional knockout mice (CKO).
Conditional lens-specific ADAM10-CKO mice where generated following outcrossing of Adam10floxed/floxed mice to the LeCre transgenic mice that express the Cre recombinase under the control of the Pax6 promoter. Adam10-CKO and control mice were further characterized at different developmental time points using slit lamp biomicroscopy, histological, EdU, TUNEL, and immunohistological analyses.
Adam10-CKO mice appeared anophthalmic with hair loss around the eyes extending to the snout region. Histological analysis of Adam10-CKO adult eyes revealed absence of the anterior chamber and poor separation between the cornea, iris, and lens tissues, thickened iris, and severe microphakia-characterized by the absence of epithelial and fiber cell structures and the presence of swollen cells at the periphery. First morphological lens abnormalities in Adam10-CKO lenses were noted at E13.5 characterized by reduced number of lens cells, thinned epithelium, and disorganized fiber cells. By 16.5 the Adam10-CKO lenses have undergone degeneration precluding further evaluation. Immunohistochemical evaluation revealed that at E13.5 Adam10-CKO lenses exhibit abberrant lens epithelial cell proliferation, aberrant lens fiber cell differentiation, without a significant increase in apoptosis.
Our results demonstrate that ADAM10 is indispensable for proper lens development. ADAM10 has been previously proposed to function as a regulator of NOTCH1 signaling. In the lens NOTCH signaling is mediated by NOTCH2 and lens-specific ablation of Notch2 or RBP-J results in premature epithelial cell cycle exit and precocious lens fiber cell differentiation. The identified Adam10-CKO lens phenotypes suggest disrupted NOTCH signaling, although studies confirming disrupted NOTCH2 signaling are currently under way.
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