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Bhagwat V. Alapure, Jamie Stull, Zeynep Firtina, Melinda K. Duncan; UPR Is Relieved With Age In Connexin50 Mutant Mice. Invest. Ophthalmol. Vis. Sci. 2011;52(14):1532.
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© ARVO (1962-2015); The Authors (2016-present)
We previously reported that the retention of newly synthesized collagen IV in the endoplasmic reticulum (ER) leads to high level activation of Unfold Protein Response (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 investigate UPR responses in homozygous mutant Cx50 lenses and the possible contribution of UPR to the severity of cataracts.
Embryonic, newborn and adult eyes were obtained from mice homozygous for the Cx50S50P and Cx50G22R alleles. The expression of UPR markers in comparison to wild type controls was assessed by immunolocalization.
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 retain Cx50 in the ER, and upregulate the expression of the ER resident chaperone BiP compared to wildtype lenses during embryogenesis, with maximum levels detected at birth. However, as mice age, less Cx50 protein is found in the ER and the expression of UPR markers falls to levels similar to that seen in normal lenses.
UPR is activated in developing connexin50 mutant lenses but is relieved postnatally, likely due to changes in the ability of the lens to clear this mutant protein from the ER.
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