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A Cdc42/RhoA regulatory circuit downstream of glycoprotein Ib guides transendothelial platelet biogenesis

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  • Sebastian Dütting

    (Institute of Experimental Biomedicine, University Hospital and University of Würzburg
    Rudolf Virchow Center, University of Würzburg)

  • Frederique Gaits-Iacovoni

    (INSERM UMR1048, Institut des Maladies Métaboliques et Cardiovasculaires—I2MC, UMR1048, Institut National de la Santé et de la Recherche Médicale, Université de Toulouse)

  • David Stegner

    (Institute of Experimental Biomedicine, University Hospital and University of Würzburg)

  • Michael Popp

    (Institute of Experimental Biomedicine, University Hospital and University of Würzburg
    Rudolf Virchow Center, University of Würzburg)

  • Adrien Antkowiak

    (INSERM UMR1048, Institut des Maladies Métaboliques et Cardiovasculaires—I2MC, UMR1048, Institut National de la Santé et de la Recherche Médicale, Université de Toulouse)

  • Judith M.M. van Eeuwijk

    (Institute of Experimental Biomedicine, University Hospital and University of Würzburg
    Rudolf Virchow Center, University of Würzburg)

  • Paquita Nurden

    (Institute of Experimental Biomedicine, University Hospital and University of Würzburg
    Institut Hospitalo-Universitaire LIRYC, Plateforme Technologique d’Innovation Biomédicale, Hôpital Xavier Arnozan)

  • Simon Stritt

    (Institute of Experimental Biomedicine, University Hospital and University of Würzburg
    Rudolf Virchow Center, University of Würzburg)

  • Tobias Heib

    (Institute of Experimental Biomedicine, University Hospital and University of Würzburg
    Rudolf Virchow Center, University of Würzburg)

  • Katja Aurbach

    (Institute of Experimental Biomedicine, University Hospital and University of Würzburg
    Rudolf Virchow Center, University of Würzburg)

  • Oguzhan Angay

    (Rudolf Virchow Center, University of Würzburg)

  • Deya Cherpokova

    (Institute of Experimental Biomedicine, University Hospital and University of Würzburg
    Rudolf Virchow Center, University of Würzburg)

  • Niels Heinz

    (Research Group for Gene Modification in Stem Cells, LOEWE Center for Cell and Gene Therapy Frankfurt/Main and the Paul-Ehrlich-Institute)

  • Ayesha A. Baig

    (Institute of Experimental Biomedicine, University Hospital and University of Würzburg
    Rudolf Virchow Center, University of Würzburg)

  • Maximilian G. Gorelashvili

    (Institute of Experimental Biomedicine, University Hospital and University of Würzburg
    Rudolf Virchow Center, University of Würzburg)

  • Frank Gerner

    (Institute of Experimental Biomedicine, University Hospital and University of Würzburg
    Rudolf Virchow Center, University of Würzburg)

  • Katrin G. Heinze

    (Rudolf Virchow Center, University of Würzburg)

  • Jerry Ware

    (University of Arkansas for Medical Sciences)

  • Georg Krohne

    (Biocenter, University of Würzburg)

  • Zaverio M. Ruggeri

    (The Scripps Research Institute)

  • Alan T. Nurden

    (Institut Hospitalo-Universitaire LIRYC, Plateforme Technologique d’Innovation Biomédicale, Hôpital Xavier Arnozan)

  • Harald Schulze

    (Institute of Experimental Biomedicine, University Hospital and University of Würzburg)

  • Ute Modlich

    (Research Group for Gene Modification in Stem Cells, LOEWE Center for Cell and Gene Therapy Frankfurt/Main and the Paul-Ehrlich-Institute)

  • Irina Pleines

    (Institute of Experimental Biomedicine, University Hospital and University of Würzburg
    Rudolf Virchow Center, University of Würzburg)

  • Cord Brakebusch

    (BRIC, Biomedical Institute, University of Copenhagen)

  • Bernhard Nieswandt

    (Institute of Experimental Biomedicine, University Hospital and University of Würzburg
    Rudolf Virchow Center, University of Würzburg)

Abstract

Blood platelets are produced by large bone marrow (BM) precursor cells, megakaryocytes (MKs), which extend cytoplasmic protrusions (proplatelets) into BM sinusoids. The molecular cues that control MK polarization towards sinusoids and limit transendothelial crossing to proplatelets remain unknown. Here, we show that the small GTPases Cdc42 and RhoA act as a regulatory circuit downstream of the MK-specific mechanoreceptor GPIb to coordinate polarized transendothelial platelet biogenesis. Functional deficiency of either GPIb or Cdc42 impairs transendothelial proplatelet formation. In the absence of RhoA, increased Cdc42 activity and MK hyperpolarization triggers GPIb-dependent transmigration of entire MKs into BM sinusoids. These findings position Cdc42 (go-signal) and RhoA (stop-signal) at the centre of a molecular checkpoint downstream of GPIb that controls transendothelial platelet biogenesis. Our results may open new avenues for the treatment of platelet production disorders and help to explain the thrombocytopenia in patients with Bernard–Soulier syndrome, a bleeding disorder caused by defects in GPIb-IX-V.

Suggested Citation

  • Sebastian Dütting & Frederique Gaits-Iacovoni & David Stegner & Michael Popp & Adrien Antkowiak & Judith M.M. van Eeuwijk & Paquita Nurden & Simon Stritt & Tobias Heib & Katja Aurbach & Oguzhan Angay , 2017. "A Cdc42/RhoA regulatory circuit downstream of glycoprotein Ib guides transendothelial platelet biogenesis," Nature Communications, Nature, vol. 8(1), pages 1-13, August.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms15838
    DOI: 10.1038/ncomms15838
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