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Megakaryocyte-specific Profilin1-deficiency alters microtubule stability and causes a Wiskott–Aldrich syndrome-like platelet defect

Author

Listed:
  • Markus Bender

    (University Hospital, University of Würzburg, Würzburg 97080
    Brigham and Women’s Hospital, Harvard Medical School)

  • Simon Stritt

    (University Hospital, University of Würzburg, Würzburg 97080
    Rudolf Virchow Centre, University of Würzburg, Würzburg 97080, Germany)

  • Paquita Nurden

    (University Hospital, University of Würzburg, Würzburg 97080
    Plateforme Technologique d'Innovation Biomédicale, Hôpital Xavier Arnozan)

  • Judith M. M. van Eeuwijk

    (University Hospital, University of Würzburg, Würzburg 97080
    Rudolf Virchow Centre, University of Würzburg, Würzburg 97080, Germany)

  • Barbara Zieger

    (University Medical Centre Freiburg, Freiburg 79106)

  • Karim Kentouche

    (Jena University Hospital, Jena 07743)

  • Harald Schulze

    (University Hospital, University of Würzburg, Würzburg 97080)

  • Henner Morbach

    (University Hospital Würzburg)

  • David Stegner

    (University Hospital, University of Würzburg, Würzburg 97080
    Rudolf Virchow Centre, University of Würzburg, Würzburg 97080, Germany)

  • Katrin G. Heinze

    (Rudolf Virchow Centre, University of Würzburg, Würzburg 97080, Germany)

  • Sebastian Dütting

    (University Hospital, University of Würzburg, Würzburg 97080
    Rudolf Virchow Centre, University of Würzburg, Würzburg 97080, Germany)

  • Shuchi Gupta

    (University Hospital, University of Würzburg, Würzburg 97080
    Rudolf Virchow Centre, University of Würzburg, Würzburg 97080, Germany)

  • Walter Witke

    (Institute of Genetics, University of Bonn, Bonn 53115)

  • Hervé Falet

    (Brigham and Women’s Hospital, Harvard Medical School)

  • Alain Fischer

    (Unité d'Immunologie et d'Hématologie Pédiatrique, Hôpital Universitaire Necker-Enfants Malades)

  • John H. Hartwig

    (Brigham and Women’s Hospital, Harvard Medical School)

  • Bernhard Nieswandt

    (University Hospital, University of Würzburg, Würzburg 97080
    Rudolf Virchow Centre, University of Würzburg, Würzburg 97080, Germany)

Abstract

Wiskott–Aldrich syndrome (WAS) is caused by mutations in the WAS gene and is characterized by immunodeficiency, eczema and microthrombocytopenia. The molecular link between WAS mutations and microthrombocytopenia is unknown. Profilin1 (Pfn1) is a key actin-regulating protein that, besides actin, interacts with phosphoinositides and multiple proline-rich proteins, including the WAS protein (WASp)/WASp-interacting protein (WIP) complex. Here we report that mice with a megakaryocyte/platelet-specific Pfn1 deficiency display microthrombocytopenia due to accelerated turnover of platelets and premature platelet release into the bone marrow. Both Pfn1-null mouse platelets and platelets isolated from WAS patients contained abnormally organized and hyperstable microtubules. These results reveal an unexpected function of Pfn1 as a regulator of microtubule organization and point to a previously unrecognized mechanism underlying the platelet formation defect in WAS patients.

Suggested Citation

  • Markus Bender & Simon Stritt & Paquita Nurden & Judith M. M. van Eeuwijk & Barbara Zieger & Karim Kentouche & Harald Schulze & Henner Morbach & David Stegner & Katrin G. Heinze & Sebastian Dütting & S, 2014. "Megakaryocyte-specific Profilin1-deficiency alters microtubule stability and causes a Wiskott–Aldrich syndrome-like platelet defect," Nature Communications, Nature, vol. 5(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms5746
    DOI: 10.1038/ncomms5746
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