Abstract
Purpose :
To investigate the underlying mechanisms of light scattering in inner lens fibers of connexin 46 (Cx46) and connexin 50 (Cx50) mutant mice; to characterize the genetic variants that facilitate or alleviate age-related cataract severity; and to determine the molecular components that directly or indirectly cause light scattering in lens fibers.
Methods :
Laser confocal microscopy, X-ray tomography and optical coherence tomography were used to characterize the morphological changes of fiber cells and cataract formation in vitro and in vivo. Biochemical analysis was used to examine the protein changes in lens fibers of normal and cataract lenses. Genetic linkage examination and gene SNP DNA analysis were used to determine the genetic modifiers in cataractogenesis among different mouse strain backgrounds.
Results :
Confocal images reveal disrupted shape and surface interlocking structures of lens fiber cells, protrusions occurred prior to the progression of cataract formation, and the presence of extensive WGA-positive membrane aggregates and F-actin-positive aggregates of irregularly shaped and sized inner fibers, which associated with dense light scattering in the lens core. Increased crystallin protein degradation and calcium deposits were correlated with the progression and severity of Cx46KO cataractous lenses while abnormal vesicle-like structures and lens core fiber degeneration were associated with Cx50KO cataractous lenses. Genetic evidence show that the cytoskeletal and scaffold proteins including periaxin and CP49 act as genetic modifiers to influence cataract formation.
Conclusions :
Aberrant aggregates of fiber cell membrane-cytoskeleton complexes, calcium deposits, and other factors contribute to light scattering in Cx46KO lenses among different mouse strains. Disruptions of lens gap junction, adhesion complexes and cytoskeletal-associated proteins can synergistically promote the cataract formation. Abnormal vesicle-like structures and degenerative fibers likely cause abnormal light scattering in Cx50KO lenses. Mechanistic differences between Cx46 and Cx50 in maintaining the homeostasis and morphogenesis of inner fiber cells need to be further investigated.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.