The role of Unfolded Protein Response in lens pathology and physiology.

摘要

The lens is enclosed by the capsule, a specialized extracellular matrix that serves as a semi-permeable barrier and mechanical scaffold for lens cells. Collagen IV is the most abundant component of the lens capsule and is essential for basement membrane stability. Individual Collagen IV chains are synthesized, modified and assembled into triple helical protomers in the endoplasmic reticulum of lens cells, and are secreted into the matrix through the secretory pathway. Notably, in several human diseases and mouse models, collagen mutations are associated with an increased risk of cataract and lens capsular rupture. However, the underlying mechanisms of cataract pathogenesis in these conditions are still unknown.;My research aims at determining the role of ER-stress signaling pathway known as Unfolded Protein Response in lens pathology caused by abnormal collagen retention in the secretory pathway. Using two different mouse models, I showed that mutations or ectopic expression of individual collagen genes can result in the accumulation of unfolded collagen chains in the secretory pathway and activation of the Unfolded Protein Response (UPR). Transgenic mice expressing ectopic Col4a3 or Col4a4 genes in the lens exhibited activation of IRE1, ATF6 and PERK pathways associated with expansion of the endoplasmic reticulum and attenuation of general protein translation. The expression of the transgenes had adverse effects on lens fiber cell differentiation and eventually induced cell death in a group of transgenic fiber cells. In Col4a1+/Deltaex40 mutant mice, the accumulation of mutant chains also caused low levels of UPR activation. However, cell death was not induced in mutant lenses suggesting that low levels of UPR activation are not pro-apoptotic. Collectively, the results provide in vivo evidence for a role of UPR in cataract formation in response to accumulation of terminally unfolded proteins in the endoplasmic reticulum.;Interestingly, this study also demonstrated that UPR is activated during normal lens development. I detected the activation of three UPR markers, IRE1, ATF6 and PERK in wild type FVB/N mice starting at E12.5. The highest expression was seen in the youngest fiber cells at the lens periphery suggesting UPR activation might be necessary in early lens fiber cell differentiation.;Overall, this work proposes that UPR activation is necessary for normal development; however, its over activation due to unfolded collagen accumulation could be a contributing factor to lens pathological conditions such as cataracts.