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

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, Deya Cherpokova, Niels Heinz, Ayesha A. Baig, Maximilian G. Gorelashvili, Frank Gerner, Katrin G. Heinze, Jerry Ware, Georg Krohne, Zaverio M. Ruggeri, Alan T. Nurden, Harald Schulze, Ute Modlich, Irina Pleines, Cord Brakebusch and Bernhard Nieswandt ()
Additional contact information
Sebastian Dütting: Institute of Experimental Biomedicine, University Hospital and 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
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
Paquita Nurden: Institute of Experimental Biomedicine, University Hospital and University of Würzburg
Simon Stritt: Institute of Experimental Biomedicine, University Hospital and University of Würzburg
Tobias Heib: Institute of Experimental Biomedicine, University Hospital and University of Würzburg
Katja Aurbach: Institute of Experimental Biomedicine, University Hospital and University of Würzburg
Oguzhan Angay: Rudolf Virchow Center, University of Würzburg
Deya Cherpokova: Institute of Experimental Biomedicine, University Hospital and 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
Maximilian G. Gorelashvili: Institute of Experimental Biomedicine, University Hospital and University of Würzburg
Frank Gerner: Institute of Experimental Biomedicine, University Hospital and 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
Cord Brakebusch: BRIC, Biomedical Institute, University of Copenhagen
Bernhard Nieswandt: Institute of Experimental Biomedicine, University Hospital and University of Würzburg

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms15838

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