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Melinda K Duncan, Mallika Pathania, Yan Wang; Beta1 integrin is a negative regulator of lens epithelial to fiber cell differentiation in the early lens. Invest. Ophthalmol. Vis. Sci. 201657(12):.
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© ARVO (1962-2015); The Authors (2016-present)
β1 integrin heterodimerizes with different α integrins to create cell surface receptors that detect diverse extracellular matrices (ECM) and initiate cell-cell signaling. At the latter stages of embryonic lens development, β1 integrin is essential for maintenance of lens epithelial phenotype as well lens epithelium survival (Simirski et al, 2007). However the role of β1 integrin in early lens morphogenesis is not well understood. This study investigates the role of β1 integrin in early lens development.
Mice were created homozygous for the β1 integrin floxed allele and hemizygous for Le-Cre transgene which is expressed in cells of the surface ectoderm starting at lens placode stage (β1-LE). Loss of β1 integrin protein expression was determined by immunostaining. Lens morphology was assessed by histological analysis. Expression of lens epithelial and fiber cell markers, cell signaling molecules and transcription factors were studied by immunolocalization.
Loss of β1 integrin protein from the lens vesicle (10.5 dpc) of β1-LE mice results in exit of the anterior lens epithelium (LECs) from the cell cycle. LECs also elongate towards the presumptive cornea, lose expression of E-cadherin, and initiate expression of Aquaporin 0 as well as crystallins suggesting that these cells are undergoing fiber cell differentiation. Consistent with this, β1-LE lens epithelial cells lose expression of the lens epithelial preferred transcription factors, Pax6, FoxE3 and Hes1, while these cells initiate the expression of the transcription factors cMaf and Prox1 which positively regulate lens fiber cell differentiation. β1-LE lens epithelial cells markedly upregulate Erk, Akt and Smad 1/5/8 phosphorylation compared to controls indicative of ectopic activation of BMP and FGF signaling in the lens.
Our data suggests that shortly after lens vesicle closure, β1 integrin blocks inappropriate differentiation of the lens epithelium into fibers, likely due to its ability to interfere with BMP and/or FGF receptor activation. Notably, North et al, 2015 has shown that, in other cell types, β1-integrins can sequester BMP receptors away from lipid rafts, which can in turn limit FGF receptor expression. Thus, β1 integrin appears to play an important role in fine-tuning the response of the early lens to the gradient of FGFs that regulate the differentiation of primary lens fibers.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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