Abstract
The basis for mammalian lens fiber cell organization, transparency, and biomechanical properties has contributions from two specialized cytoskeletal systems: the spectrin-actin membrane skeleton and beaded filament cytoskeleton. The spectrin-actin membrane skeleton predominantly consists of α2β2-spectrin strands interconnecting short, tropomyosin-coated actin filaments, which are stabilized by pointed-end capping by tropomodulin 1 (Tmod1) and structurally disrupted in the absence of Tmod1. The beaded filament cytoskeleton consists of the intermediate filament proteins CP49 and filensin, which require CP49 for assembly and contribute to lens transparency and biomechanics. To assess the simultaneous physiological contributions of these cytoskeletal networks and uncover potential functional synergy between them, we subjected lenses from mice lacking Tmod1, CP49, or both to a battery of structural and physiological assays to analyze fiber cell disorder, light scattering, and compressive biomechanical properties. Findings show that deletion of Tmod1 and/or CP49 increases lens fiber cell disorder and light scattering while impairing compressive load-bearing, with the double mutant exhibiting a distinct phenotype compared to either single mutant. Moreover, Tmod1 is in a protein complex with CP49 and filensin, indicating that the spectrin-actin network and beaded filament cytoskeleton are biochemically linked. These experiments reveal that the spectrin-actin membrane skeleton and beaded filament cytoskeleton establish a novel functional synergy critical for regulating lens fiber cell geometry, transparency, and mechanical stiffness.
Highlights
The ocular lens consists of successive layers of hexagonally packed fiber cells, whose structural properties provide lens transparency [1]
Our findings show that deletion of both tropomodulin 1 (Tmod1) and CP49 results in defects in lens fiber cell organization, light scattering, and compressive mechanical properties that are distinct from defects arising from deletion of either Tmod1 or CP49 alone
The Tmod12/2Tg+ mouse is on a mixed FvBN/129FvJ/C57Bl6 background with an endogenous mutation in the Bfsp2/CP49 gene, resulting in the absence of CP49 (CP492/2), concomitantly reduced levels of filensin, and no beaded filament cytoskeleton [18,20,35,41]
Summary
The ocular lens consists of successive layers of hexagonally packed fiber cells, whose structural properties provide lens transparency [1]. The lens fiber cells remain radially aligned and hexagonally packed throughout differentiation in the cortex, with their membranes developing increasingly elaborate morphological protrusions to form large paddle-like structures in the deep cortex, which are remodeled into smoother membrane contours in the organelle-free fiber cells of the lens nucleus [6,7,8,9,10] This stereotypic growth process is believed to be important for establishing the biomechanical properties of the mature lens, which, during focusing and accommodation, withstands frequent mechanical loading imposed by the ciliary muscle and transmitted to the lens via the ciliary zonule [11]
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