Wednesday, November 20, 2013, 10:00am – 11:30am, in 489 Minor Hall

Cytoskeletal Synergy in Lens Physiology and Pathology

presented by

Velia M. Fowler, Ph.D.
Professor Department of Cell and Molecular Biology
The Scripps Research Institute

 

The shape and transparency of the vertebrate lens depends on a stereotyped morphogenetic program of fiber cell differentiation that results in long thin fiber cells shaped like flattened hexagons in cross-section. The exquisite regularity of fiber cell geometry and the stereotypic program of fiber cell maturation and aging provides an excellent system to study the role of the cytoskeleton in membrane domain assembly, lens morphogenesis, transparency and mechanics. Lens transparency also depends critically on fiber cell gap junction proteins (connexins) which assemble into membrane subdomains that control ionic homeostasis in the avascular lens; mutations in lens connexins (Cx46, Cx50) in humans and mice result in loss of lens transparency and cataracts, which are a major cause of blindness worldwide. Lens fiber cells contain two membrane-associated cytoskeletal systems: specialized intermediate filaments termed beaded filaments, and a tropomodulin1 (Tmod1)-stabilized spectrin-actin network. We have shown that combined absence of Tmod1 and beaded filaments in the mouse lens leads to extensive disruption of the spectrin-actin network, with synergistic effects on lens fiber cell regular packing, lens transparency and mechanics (Gokhin et al., PLoS ONE 7(11): e48734, 2012). Strikingly, in wild-type lenses, we discovered recently that the spectrin-actin network completely surrounds the large gap junction plaques, such that the connexins are located precisely in gaps of the spectrin-actin network. By contrast, in double knockout lenses with no beaded filaments and a disrupted spectrin-actin network, the plaques are dispersed to smaller puncta. Moreover, electrophysiology assays on whole lenses show that ionic homeostasis and gap junction coupling conductance is impaired in the double knockout mutant lenses. Our work suggests that the spectrin-actin network and beaded filament cytoskeletons synergize to control lens structure and function, including stability of gap junction plaque membrane subdomains, lens ionic homeostasis, fiber cell morphologies and whole lens mechanics. Dysfunction in these cytoskeletal systems may contribute to decreases in lens transparency as well as age-dependent increases in lens stiffness in presbyopia.

 

Host: Xiaohua Gong

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