Blood Journal
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Altered microtubule equilibrium and impaired thrombus stability in mice lacking RanBP10

  1. Imke Meyer1,2,
  2. Stefan Kunert2,3,
  3. Silke Schwiebert2,
  4. Ina Hagedorn4,
  5. Joseph E. Italiano Jr5,
  6. Sebastian Dütting4,
  7. Bernhard Nieswandt4,
  8. Sebastian Bachmann6, and
  9. Harald Schulze2,7
  1. 1Department of Biochemistry, Berlin, Germany;
  2. 2Laboratory of Pediatric Molecular Biology, Charité Medical School, Berlin, Germany;
  3. 3Max Delbrück Center, Berlin Buch, Germany;
  4. 4Rudolf-Virchow Center, Würzburg, Germany;
  5. 5Brigham and Women's Hospital, Harvard Medical School Boston, MA;
  6. 6Department of Anatomy, Charité, Berlin, Germany; and
  7. 7HLA Tissue Typing Laboratory, Institute for Transfusion Medicine, Charité, Berlin, Germany

Abstract

The crucial function of blood platelets in hemostasis is to prevent blood loss by stable thrombus formation. This process is driven by orchestrated mechanisms including several signal transduction cascades and morphologic transformations. The cytoplasmic microtubule modulator RanBP10 is a Ran and β1-tubulin binding protein that is essential for platelet granule release and mice lacking RanBP10 harbor a severe bleeding phenotype. In this study, we demonstrate that RanBP10-nullizygous platelets show normal adhesion on collagen and von Willebrand factor under flow conditions. However, using a ferric chloride-induced arterial thrombosis model, the formation of stable thrombi was significantly impaired, preventing vessel occlusion or leading to recanalization and thromboembolization. Delta-granule secretion was normal in mutant mice, whereas platelet shape change in aggregometry was attenuated. Lack of RanBP10 leads to increased β1-tubulin protein, which drives α-monomers into polymerized microtubules. In mutant platelets agonists failed to contract the peripheral marginal band or centralize granules. Pretreatment of wild-type platelets with taxol caused microtubule stabilization and phenocopied the attenuated shape change in response to collagen, suggesting that RanBP10 inhibits premature microtubule polymerization of β1-tubulin and plays a pivotal role in thrombus stabilization.

  • Submitted January 13, 2012.
  • Accepted August 14, 2012.
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