Hemostatic, inflammatory, and fibroblast responses are blunted in mice lacking gelsolin

Abstract

Gelsolin, an 82 kDa actin-binding protein, has potent actin filament-severing activity in vitro. To investigate the in vivo function of gelsolin, transgenic gelsolin-null (Gsn-) mice were generated and found to have normal embryonic development and longevity. However, platelet shape changes are decreased in Gsn- mice, causing prolonged bleeding times. Neutrophil migration in vivo into peritoneal exudates and in vitro is delayed. Gsn- dermal fibroblasts have excessive actin stress fibers and migrate more slowly than wild-type fibroblasts, but have increased contractility in vitro. These observations establish the requirement of gelsolin for rapid motile responses in cell types involved in stress responses such as hemostasis, inflammation, and wound healing. Neither gelsolin nor other proteins with similar actin filament-severing activity are expressed in early embryonic cells, indicating that this mechanism of actin filament dynamics is not essential for motility during early embryogenesis.

Cell biology of embryonic migration

“…Mouse knockouts of cell migration components or other proteins with direct effects on cell migration Protein Function Type Phenotype Reference α skeletal muscle actin Actin Cytoskeleton Total Postnatal death at P1-9, marked loss of body weight; upregulation of other actin isoforms (Crawford et al, 2002) α smooth muscle actin Actin Cytoskeleton Total Viable; impaired vascular contractility and blood pressure homeostasis; upregulation of other actin isoforms (Schildmeyer et al, 2000) α cardiac actin Actin Cytoskeleton Total Perinathal lethality; cardiac hypertrophy and heart muscle abnormalities; upregulation of other actin isoforms (Kumar et al, 1997) β non-muscle actin Actin Cytoskeleton Total Death after E9.5 (Shawlot et al, 1998) γ non-muscle actin Actin Cytoskeleton Skeletal muscle-specific Muscle weakness, necrosis and degeneration (Sonnemann et al, 2006) Tropomyosin Actin Cytoskeleton Total Death before morula stage (Hook et al, 2004) Mena Actin Cytoskeleton Total Viable, with misrouted axons and defects in the nervous system (Lanier et al, 1999) Mena, VASP, Evl triple null Actin Cytoskeleton Total Defects in brain development, neuritogenesis, and neural tube closure Filamin-B Actin Cytoskeleton Total Skeletal malformations and impaired microvascular development (Zhou et al, 2007) Gelsolin (or ADF) Actin Cytoskeleton Total Defects in fibroblast and platelet motility and lamellar responses (Witke et al, 1995) Nonmuscle myosin II-B Actin Cytoskeleton Total Embryonic and perinatal lethality with severe heart defects (Tullio et al, 1997) Myosin heavy chain II-A Actin Cytoskeleton Total Failure in embryonic patterning, embryonic lethality by E7.5 (Conti et al, 2004) Cardiac alpha myosin, heavy chain Actin Cytoskeleton Total Embryonic lethality between E11 and 12 with gross heart defects (Jones, 1996) (Imamoto and Soriano, 1993;Nada et al, 1993) Ephrin B1 Transmembrane signaling Total Neural crest cell misguidance (cranial and cardiac, but not trunk) (Davy et al, 2004) Angiomotin Transmembrane signaling Total Death between E11-E11.5, severe vascular insufficiency in intersomitic regions, dilated vessels in the brain (Aase et al, 2007) Birth Defects Res C Embryo Today. Author manuscript; available in PMC 2009 June 1.…”

Regulation of Cell Motility by Tyrosine Phosphorylated Villin

“…Overexpression of other proteins of the villin superfamily, including gelsolin and CapG have been demonstrated to increase the motile phenotypes of cells (Hartwig et al, 1989;Sun et al, 1995;Aizawa et al, 1996;Chen et al, 1996;Furnish et al, 2001). Conversely, the gelsolin-null mice and other mutant cell lines lacking these proteins have been shown to exhibit decreased rates of cell motility (Witke et al, 1995;Lu et al, 1997;Chellaiah et al, 2000). To confirm our hypothesis that villin and its ligand-binding activities described by in vitro experiments are mechanistically important to villin's relationship to cell motility, we used the villin-null HeLa cells to overexpress villin by using a tetracycline-regulated system.…”

Selective Inhibition of IgG-Mediated Phagocytosis in Gelsolin-Deficient Murine Neutrophils

“…Phagocytosis was assayed in suspension and not with adherent cells to minimize the contribution active cell movement, which is known to be influenced by gelsolin (4). Furthermore, additional receptors may be activated upon adherence to surfaces and influence the phagocytic uptake.…”

“…Gelsolin-actin complexes dissociate in the presence of polyphosphoinositides (2,3). Gelsolin-null (Gsn Ϫ ) 5 mice have normal embryonic development and longevity (4). Gsn Ϫ mice show a prolonged bleeding time due to decreased platelet shape changes.…”