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B. P. Madakashira, B. D. Wagner, F. Wang, M. L. Robinson; Frs2 Is Required for Normal Lens Development. Invest. Ophthalmol. Vis. Sci. 2009;50(13):3482.
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FGFRs are essential for lens cell survival and differentiation. Among the Receptor Tyrosine Kinases (RTKs), FGFRs are distinct in that much of their intra-cellular signaling is mediated through a membrane anchored docking molecule, Frs2 (Fibroblast Growth Factor Receptor Substrate 2). Upon activation by FGFRs, Frs2 recruits the downstream effectors Shp2 and Grb2 that ultimately mediate the activation of AKT and ERK signaling pathways. Although FGFRs are capable of Frs2-independent signaling, Frs2 is required to achieve sustained ERK phosphorylation in response to FGF stimulation in fibroblasts. We hypothesize that Frs2 is required for FGFR-mediated lens development and have deleted Frs2 in the lens to test this hypothesis.
A conditional mutation in Frs2 where exon 10 (encoding all of the binding sites for Grb2 and Shp2) is flanked by LoxP sites was crossed onto a heterozygous LeCre background to achieve conditional deletion of Frs2 in all surface ectoderm-derived eye structures including the lens. Efficiency of deletion was assessed by immunological detection of Frs2 in eye sections. E15.5 lenses were tested for proliferation with BrDU incorporation assay, apoptosis by TUNEL assay, and for expression of phosphorylated ERK (pERK), β Crystallin and p57Kip2 by immunohistochemistry.
The Frs2 knockout lenses displayed reduced levels of total Frs2 which corresponded to decreased expression of pErk at E15.5. Proliferation was not affected significantly at E15.5, whereas a significant increase in cell death was observed. The mutant Frs2 lenses were approximately 50% smaller than wildtype lenses at E15.5 and exhibited fiber cell dysmorphology and vacuolization characterized by abnormal arrangement of cell nuclei in the bow region. The pattern of p57Kip2 was also altered in that p57Kip2 expression was abnormally expressed in some anterior epithelial cells and was retained in some maturing fiber cells.
Frs2 is required for normal lens development. Frs2 is not essential for lens induction as well as for the expression of fiber specific crystallins such as β- and γ- crystallins. Although the expression of Frs2 is significantly reduced in the mutants at E15.5, its expression is not completely lost. Frs2 may play an important role in fiber cell differentiation and in the activation of survival pathways.
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