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Actin and myosin or actomyosin filaments also play a significant role in cells other than those involved in muscle contraction (which occurs within the sarcomere of muscle cells). The mechanism of non-muscle cell contractile bundles was first observed in Dictyostelium and Acanthamoeba. In non-muscle cells, two bundles are commonly found: stress fibers and actomyosin adherence belts. These contractile bundles are smaller and less organized than the ones found in muscle cells. They  are held...
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Actin is a highly conserved cytoskeletal protein found abundantly in eukaryotic cells. It constitutes 10% weight of the total cellular protein in muscle cells, while in non-muscle cells, it is lower and makes up around 1–5 percent of the total cell protein. Actin found in the unicellular amoebae and complex multicellular animals is around 80% similar, demonstrating their conservation over a billion years of evolution.  Actin coding genes are conserved within species and across...
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Nuclear Smooth Muscle α-actin Participates in Vascular Smooth Muscle Cell Differentiation.

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Nuclear smooth muscle α-actin (αSMA) is crucial for smooth muscle cell differentiation. Pathogenic variants in ACTA2, particularly at arginine 179, disrupt this nuclear role, leading to vascular diseases.

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Area of Science:

  • Genetics
  • Cell Biology
  • Cardiovascular Research

Background:

  • Missense variants in ACTA2, encoding smooth muscle α-actin (αSMA), are linked to thoracic aortic disease.
  • Specific variants at arginine 179 (R179) cause Smooth Muscle Dysfunction Syndrome (SMDS), presenting with childhood vascular diseases.

Purpose of the Study:

  • To investigate the role of nuclear αSMA in smooth muscle cell (SMC) differentiation.
  • To determine the impact of ACTA2 R179 variants on αSMA nuclear localization and SMC function.

Main Methods:

  • Immunofluorescence microscopy to assess αSMA nuclear localization in wildtype (WT) and mutant cells.
  • In vitro and in vivo differentiation assays using primary SMCs from Acta2 mutant mice.
  • Analysis of chromatin accessibility and differentiation of patient-derived induced pluripotent stem cells.
  • Single-cell transcriptomic analysis of patient aortic tissue.

Main Results:

  • WT αSMA localizes to the nucleus in differentiating SMCs and associates with chromatin remodeling complexes.
  • The ACTA2 p.R179 variant exhibits reduced nuclear localization of αSMA.
  • Acta2 mutant SMCs show impaired differentiation and altered chromatin accessibility.
  • Patient-derived cells and tissues reveal failed SMC differentiation and increased SMC plasticity.

Conclusions:

  • Nuclear αSMA plays a critical role in SMC differentiation and gene regulation.
  • Pathogenic ACTA2 R179 variants disrupt αSMA nuclear function, contributing to SMC dysfunction and vascular disease development.