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M. K. Duncan, J. Stull, Z. Firtina; Activation of the Unfolded Protein Response (UPR) in Connexin50 Mutant Lenses. Invest. Ophthalmol. Vis. Sci. 2010;51(13):3461. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
We have previously found that retention of newly synthesized collagen IV in the endoplasmic reticulum (ER) leads to high level activation of UPR, a cell stress response pathway, resulting in cataracts. Further, it has been reported that mice harboring mutations in connexin50 (Cx50) have more severe lens phenotypes than those lacking the gene. Here we test the hypothesis that retention of mutant Cx 50 within the ER leads to robust UPR and can contribute to the increased severity of cataracts in Cx50 mutant mice.
Embryonic, newborn and adult eyes were obtained from mice homozygous for the Cx50S50P and Cx50G22R alleles. Lens morphology was assessed by darkfield microscopy and histological analysis. The expression of UPR markers in comparison to wildtype controls was assessed by western blotting, rt-PCR and immunolocalization in lens obtained from animals ranging from embryonic day 12.5 until adulthood.
As previously reported, both Cx50S50P and Cx50G22R mutant lenses are small, have an unorganized fiber cell structure, and cataract. We found that lenses from both of these genotypes begin to upregulate the expression of the ER resident chaperone BiP compared to wildtype lenses in mid-embryogenesis and this relative upregulation is robust by birth. While the full gamut of pathways responsible for this upregulation are still under investigation, the IreI pathway appears to be inappropriately activated as measured by the elevated levels of Xbp-1 splicing detected in mutant relative to wildtype lenses.
Expression of mutant transmembrane proteins in the lens can lead to the activation of UPR. This supports the hypothesis that UPR can contribute to the lens phenotypes of Cx50 mutants.
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