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Xiaohua Gong, Wiktor Stopka, Nikki Tjahjono, Chun-hong Xia; Lens stiffness and homeostasis in connexin mutant mice. Invest. Ophthalmol. Vis. Sci. 2018;59(9):4974.
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© ARVO (1962-2015); The Authors (2016-present)
This project aims to investigate how gap junctions, beaded filaments, and cytoskeleton synergistically regulate lens stiffness, homeostasis and nuclear cataract formation. The Gja3 (encodes α3 connexin or Cx46) knockout (Gja3-/-) mice display variable cataracts between the C57BL/6J (B6) and 129SvJae (129) strain backgrounds. The 129 wild-type (WT) mice lack lens beaded intermediate filaments and utilize a periaxin gene variant that encodes a cytoskeletal scaffold protein.
A modified muscle lever system was used to measure the compression of mouse lenses; lens total displacement at the point of maximum force indicated the lens stiffness. Mass-spec analysis was used to determine the metabolic profiles of WT or Gja3-/- lenses in different strain backgrounds. Lens vibratome sections were stained with various fluorescent reagents and imaged for morphological analysis.
Lens stiffness measurement was performed on WT or knockout lenses in different strain backgrounds and at various ages. The loss of Gja3 appeared to stiffen the lens, more drastically in older lenses. Both the CP49 deletion in 129 strain background and the B6-periaxin (prx) variant contribute to the lens softening. The presence of 129-prx variant seemed to stiffen the lens, which was also observed in the B6-WT CP49(B6/B6) prx(129/129) lenses. Morphological data showed that the surface topology of lens fiber cells was affected by Gja3 knockout and prx variants. Metabolite profiling revealed changes of antioxidants, glycolysis pathway intermediates and lipids compositions in Gja3-/- lenses of different strain backgrounds.
A loss of Gja3 affects the structure of fiber cell interdigitations, impairs the elasticity of fiber cells resulting in lens hardening. Metabolite changes contribute to the differences in lens homeostasis that is required for the maintenance of lens fiber cell shape and surface topology. Gap junction communication, CP49 intermediate filaments and prx-mediated cytoskeleton synergistically regulate lens stiffness and homeostasis needed for lens transparency and optical property.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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