Abstract
Presentation Description :
Purpose. To test a hypothesis that gap junctions and the cytoskeleton synergistically control lens metabolism and the surface interlocking structure of fiber cells to establish lens transparency and stiffness. To identify and characterize genetic variances in common mouse strains that influence the severity of cataracts in Gja3 knockout (-/-) mice.
Methods. Morphogenesis of lens fiber cells was characterized by confocal imaging and electron microscopic analysis. Lens phenotypes were evaluated by slit-lamp in vivo and by light scattering measure in vitro. Linkage markers were used for mapping genetic variances. Lens proteins were characterized with various biochemical and cellular techniques.
Results. Disrupted morphogenesis of mature fibers includes a loss of interlocking structures such as tongue-and-groove in Gja3-/- lenses. Both periaxin (prx) gene variances and CP49 deletion between C57BL/6J (B6) and 129SvJae (129) mouse strains manifested the severity of nuclear cataracts and lens stiffness. 129-Prx proteins were extensively associated with the membrane/F-actin network of peripheral and interior fibers while B6-Prx was restricted to peripheral differentiating fibers. The 129 Prx/F-actin complexes impaired the organization of surface interlocking structure from the vertices of hexagonally shaped fibers to disrupt organization of maturing fibers.
Conclusions. Lens gap junctions serve dual functions: one is to provide a pathway for metabolism and the other is to act as adhesion niches for the arrangement of surface interlocking structures required for lens transparency and stiffness. 129-Prx gene variance and CP49 deletion disrupted F-actin network or beaded intermediate filament to alter surface morphogenesis of lens fibers. Dysfunctional gap junctions and aberrant cytoskeletons synergistically impair lens homeostasis and the interlocking structures of maturing fibers, which trigger fiber cell degeneration mediated by calcium-dependent proteases, ultimately leading to dense nuclear cataracts.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.