June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
Role of S100A4 in non-muscle myosin II regulated actin-cytoskeletal organization in lens fibers
Author Affiliations & Notes
  • Levi Lankford
    Ophthalmology, Duke University, Durham, North Carolina, United States
  • Nikolai P Skiba
    Ophthalmology, Duke University, Durham, North Carolina, United States
  • Rupalatha Maddala
    Ophthalmology, Duke University, Durham, North Carolina, United States
  • Vasantha Rao
    Ophthalmology, Duke University, Durham, North Carolina, United States
  • Footnotes
    Commercial Relationships   Levi Lankford None; Nikolai Skiba None; Rupalatha Maddala None; Vasantha Rao None
  • Footnotes
    Support  NIH R01EY25096; P30EY005722
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 4397. doi:
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      Levi Lankford, Nikolai P Skiba, Rupalatha Maddala, Vasantha Rao; Role of S100A4 in non-muscle myosin II regulated actin-cytoskeletal organization in lens fibers. Invest. Ophthalmol. Vis. Sci. 2023;64(8):4397.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Non-muscle myosin II (NM II) plays a crucial role in lens cytoarchitecture, mechanics, and function. Though NM IIA mutations are associated with cataract development in humans, little is known about the regulation of NM II activity in the context of lens function. This study investigates the role of S100A4, a calcium and NM IIA binding protein which is distributed abundantly in a fiber-cell specific manner in the regulation of NM II activity in lens.

Methods : Well-characterized S100A4 null (-/-) mouse models maintained on C57BL/6 genetic background were used to determine how the absence of S100A4 influences NM II activity and actin-cytoskeletal organization in lens. Towards this, changes in the levels of NM IIA and IIB, actin-filament organization, NM IIA phosphorylation, G-actin/F-actin ratio, and the protein profile of cytoskeletal- and membrane-enriched fractions from six-month-old S100A4-/- clear lenses, in comparison with littermate wild-type lenses, were determined by immunofluorescence, biochemical and proteomics analyses.

Results : S100A4 -/- mice develop late onset opalescent cataract starting from eight-months-old. Six-month-old transparent S100A4-/- mouse lenses exhibit significant decrease in levels of both NM IIA and IIB in the insoluble fraction, phospho-NM IIA (Ser 1943), and accumulation of NM IIA in the lens soluble fraction relative to littermate WT lenses. Additionally, there were significant changes (≥ 2 fold, P<0.05) in the levels of β1 integrin, ZO-1, aquaporin-5, radixin, cortactin, α-adducin, NrCAM, drebrin-like protein, connexin-50, CLIC5 and α-crystallin in S100A4-/- lenses compared to littermate control lenses based on quantitative proteomics analyses of cytoskeletome, and membrane-enriched (100,000xg insoluble pellet) fractions. Moreover, S100A4-/- mouse lenses showed disruptions in actin-cytoskeletal organization and decreases in the levels of F-actin and increases in G-actin compared to littermate WT lenses. Interestingly, in S100A4-/- lenses, there was a robust upregulation of S100A5 in both neonatal and adult mice, which is undetectable in wild-type lenses.

Conclusions : Taken together, these multiple and interrelated results indicate that S100A4 plays a crucial role in maintaining lens cytoskeletal organization and cell adhesive interactions by regulating NM II filament assembly, phosphorylation, and actin polymerization.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.

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