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V. Govindarajan, D. J. Burgess, E. Siefker, R. A. Vaca; Differential Regulation of Dual Specificity MAP Kinase Phosphatases by Fibroblast Growth Factors During Lens and Corneal Development. Invest. Ophthalmol. Vis. Sci. 2009;50(13):4357.
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© ARVO (1962-2015); The Authors (2016-present)
Dual specificity mitogen-activated protein kinase (MAPK) phosphatases (DUSPs) negatively regulate MAPK activity in mammalian cells. The purpose of this study was to analyze endogenous and fibroblast growth factor (FGF) regulation of DUSP expression in ocular tissues.
DUSP expression was analyzed by reverse transcriptase-polymerase chain reaction (RT-PCR) on RNA isolated from eyes of new born mice. Tissue-specific expression of DUSPs in wild type and in transgenic mice that expressed either FGF-7, -8, -9 or -10 in their lens fiber cells was analyzed by in situ hybridization. Expression analyses were performed on ocular sections of formalin-fixed paraffin embedded heads of embryos or pups.
RT-PCR results suggested that all 12 members of the DUSP family (DUSP1-10, 16A1 and 16B1) were expressed in the murine eye at post natal day (P1). In addition, expression of Styx, a related member of the DUSP family, was also detected in ocular tissues. In situ hybridization analysis showed that DUSP1, 3, 4, 6, 8, 9 and 16A1 were expressed in the lens fiber cells. Of these, DUSP4 transcripts were localized to the lens epithelium at P1 and the rest were upregulated in the differentiating fiber cells at the transition zone at E15.5 and at P1. None of the DUSPs analyzed were expressed at detectable levels in the corneal epithelial and stromal cells. FGFs such as FGF8 and 9 that can signal through FGF receptor 2IIIc (FGFR2IIIc) and initiate premature lens fiber differentiation in transgenic mice upregulated DUSP4 and Styx transcription in the lens but not in the cornea. FGFs such as FGF7 and 10 that can signal through FGFR2IIIb and initiate glandular differentiation in the corneal epithelia of transgenic mice upregulated DUSP6 and Styx transcription in the cornea but not in the lens.
The distinctive expression pattern of DUSPs in the lens and cornea suggests unique roles for these enzymes in regulation of the lens and corneal differentiation programs. Interestingly, DUSP6, the most well-studied downstream target of FGF signaling, is upregulated in the cornea but not in the lens in response to FGF stimulation. These results suggest that DUSP6 expression in the lens is not likely to be mediated by an FGF. In addition, our results also suggest that signaling mediated by different FGF receptor isoforms differentially regulate DUSP expression in the lens and corneal epithelial cells.
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