title: Lens ER-stress response during cataract development in Mip-mutant mice.
abstract: Major intrinsic protein (MIP) is a functional water-channel (AQP0) that also plays a key role in establishing lens fiber cell architecture. Genetic variants of MIP have been associated with inherited and age-related forms of cataract; however, the underlying pathogenic mechanisms are unclear. Here we have used lens transcriptome profiling by microarray-hybridization and qPCR to identify pathogenic changes during cataract development in Mip-mutant (Lop/+) mice. In postnatal Lop/+ lenses (P7) 99 genes were up-regulated and 75 were down-regulated (>2-fold, p=<0.05) when compared with wild-type. A pathway analysis of up-regulated genes in the Lop/+ lens (P7) was consistent with endoplasmic reticulum (ER)-stress and activation of the unfolded protein response (UPR). The most up-regulated UPR genes (>4-fold) in the Lop/+ lens included Chac1>Ddit3>Atf3>Trib3>Xbp1 and the most down-regulated genes (>5-fold) included two anti-oxidant genes, Hspb1 and Hmox1. Lop/+ lenses were further characterized by abundant TUNEL-positive nuclei within central degenerating fiber cells, glutathione depletion, free-radical overproduction, and calpain hyper-activation. These data suggest that Lop/+ lenses undergo proteotoxic ER-stress induced cell-death resulting from prolonged activation of the Eif2ak3/Perk-Atf4-Ddit3-Chac1 branch of the UPR coupled with severe oxidative-stress.
authors.affiliation: Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Yuefang
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Bennett
authors.affiliation: Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: shiels@vision.wustl.edu.
authors.forename: Alan
authors.initials: A
authors.lastname: Shiels
mesh_terms: D000818:Animals; D020346:Aquaporins / Q000235:genetics / Q000378:metabolism*; D002386:Cataract / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D059865:Endoplasmic Reticulum Stress; D005136:Eye Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D007908:Lens, Crystalline / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D018384:Oxidative Stress; D056811:Unfolded Protein Response; D015854:Up-Regulation
chemical_list: D020346:Aquaporins; D005136:Eye Proteins; C030328:aquaporin 0
keywords: Cataract; Lens; Mouse; Oxidative stress; Unfolded protein response