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Catherine Cheng, Roberta B Nowak, Velia M Fowler; F-actin stabilizing proteins, tropomodulin 1 and γ-tropomyosin, play diverse roles in maintaining lens cell morphology, biomechanical integrity and transparency. Invest. Ophthalmol. Vis. Sci. 2017;58(8):2478.
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© ARVO (1962-2015); The Authors (2016-present)
Lens fiber cells assemble diverse F-actin networks at their plasma membranes, including a spectrin-actin network. The spectrin-actin network contains two F-actin-stabilizing proteins, tropomodulin1 (Tmod1), which caps filament ends, and γ-tropomyosin (γTM), which binds along filament sides, preventing disassembly. To elucidate the role of the F-actin cytoskeleton at the cellular (cell packing and morphology) and tissue levels (transparency, refraction and biomechanics) in the lens, we compared the phenotypes of lenses with loss of Tmod1 or γTM to reveal common or divergent roles for these actin-binding proteins in the lens.
We used biochemistry, immunohistochemistry, whole lens microscopy and tissue mechanical testing, to study mouse lenses with genetic disruption of Tmod1 or γTM.
Genetic deletion of Tmod1 leads to reduced γTM protein levels and disruption of the spectrin-actin membrane skeleton with abnormal fiber cell membrane interdigitations. Tmod1 knockout lenses are transparent, but display reduced lens stiffness at low mechanical loads. Unexpectedly, genetic depletion of γTM does not phenocopy loss of Tmod1. Instead, γTM mutant lenses have subtle and progressive anterior cataracts with reduced lens stiffness under compression at high loads and impaired recovery of lens shape after release of external load (resilience). Western blots reveal a small loss of Tmod1 in γTM mutant lenses. While fiber cell packing in the lens cortex appears normal in mutant γTM lenses, mature fiber cells have aberrant F-actin and increased cytoplasmic Tmod1 staining.
In summary, disruption of Tmod1 leads to decreased lens stiffness at low loads and attenuated fiber cell membrane interdigitations, while loss of γTM causes anterior cataracts, and lens stiffness changes at high loads with abnormal resilience. The disparate phenotypes of these mutant lenses imply that diverse F-actin networks are required for cellular level coordination, including normal fiber cell packing and morphology, as well as tissue level properties, including transparency, stiffness and resilience.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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