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Venkatesh Govindarajan, Murali R. Kuracha, Daniel Burgess, Ed Siefker, Jake T. Cooper, Michael L. Robinson, Jonathan D. Licht; Spry1 and Spry2 are Necessary for Lens Vesicle Separation and Corneal Differentiation. Invest. Ophthalmol. Vis. Sci. 2011;52(14):5884.
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© ARVO (1962-2015); The Authors (2016-present)
Sproutys (Sprys) are downstream targets and negative feedback regulators of the fibroblast growth factor (FGF) signaling pathway in multiple vertebrate organ rudiments. The purpose of this study was to analyze the roles of Sproutys (Sprys) in regulation of lens differentiation.
Expression of Spry1 and Spry2 were examined in wild type, FGF transgenic and FGF receptor (FGFR) mutant mice by in situ hybridization. Spry1 and Spry2 were conditionally deleted in the lens and corneal epithelial precursors using the Le-Cre transgene and floxed alleles of Spry1 and Spry2. Alterations in lens and corneal development were assessed by hematoxylin and eosin staining, in situ hybridization and immunohistochemistry.
Spry1 and Spry2 were upregulated in the FGF transgenic lenses and downregulated in FGFR mutant lenses. Spry1 and Spry2 single or double null lenses failed to separate from the overlying ectoderm and showed persistent kerato-lenticular stalks similar to that seen in Peters’ anomaly in humans. Apoptosis of stalk cells, normally seen during lens vesicle detachment from the ectoderm, was inhibited in Spry mutant lenses with concomitant ERK activation and upregulation of FGF-Ras-ERK targets such as Erm, Pea3 and DUSP6. Spry mutant lens epithelial cells upregulated Prox1 and p57KIP2. However, terminal differentiation markers such as β- or γ-crystallin were not induced. Lens fiber differentiation in Spry mutants was not affected. Spry mutant corneal epithelial precursors showed increased proliferation with elevated expression of Erm, DUSP6, cyclin D2 and decreased expression of the corneal differentiation marker K12.
Collectively, our results indicate that Spry1 and Spry2 1) are targets of FGF signaling in the lens, 2) through negative modulation of ERK allow lens vesicle separation and suppress premature fiber differentiation and 3) function redundantly in the corneal epithelial cells to suppress proliferation.
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