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Xiaohua Gong, Chun-hong Xia, Eddie Wang, Wiktor Stopka; Gap Junctions and Periaxin Synergistically Control Lens Fiber Cell Morphogenesis and Cataractogenesis. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):4840.
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© ARVO (1962-2015); The Authors (2016-present)
Gja3 (connexin 46) mutations cause various types of cataracts in human and mice. Recently, we have identified that variances of the periaxin (Prx) gene, encoding a scaffold protein, are associated with the severity of nuclear cataracts in Gja3 knockout (-/-) mice between the C57BL/6J (B6) strain and 129SvJae (129) strain backgrounds. The goal of our study is to determine the molecular and cellular mechanisms for how the periaxin gene variances manifest cataractogenesis in Gja3-/- lenses as well as the functions of periaxin variances in wild-type lenses.
Cataract severity was evaluated by slit-lamp examination in vivo and quantified by measuring lens light scattering in vitro. Immunohistochemical experiments were performed to study the molecular and cellular changes in different lenses; gap junction properties and the expression of Prx and cytoskeletal proteins in vivo or in vitro (transfected plasmids) were examined by biochemical and cellular approaches as well as confocal imaging.
Prx gene variances reveal the substitution of four amino acid residues between 129 and B6 strains. The 129-Prx proteins are extensively associated with the membrane/cytoskeleton of both lens peripheral and interior fiber cells while the B6-Prx proteins only appear in peripheral differentiating fibers. The 129-Prx proteins are co-immunoprecipitated with many membrane/cytoskeletal proteins. Western blotting confirms a drastic reduction of B6-Prx in the lenses. High resolution confocal images of various markers reveal that fiber cell morphogenesis, including the ball/sockets and protrusions, during development or cell maturation is regulated by Prx and manifested by 129- or B6-Prx with or without Gja3 and CP49.
Gap junctions control lens fiber cell morphogenesis by regulating the assembly and stability of membrane-cytoskeleton network via physical interactions of connexin C-terminus and homeostasis of small molecules. Prx spatially and temporally regulates membrane-cytoskeleton network to control fiber cell morphogenesis. Dysfunctions of gap junctions and Prx synergistically disrupt membrane/cytoskeleton to alter fiber cell morphogenesis and lens homeostasis thus leading to aberrant activation of calcium-dependent protease, which further impairs fiber cell surface structures and leads to severe cataract formation associated with crystallin degradation.
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