A Cdc42/RhoA regulatory circuit downstream of glycoprotein Ib guides transendothelial platelet biogenesis
Duetting S, Gaits-Iacovoni F, Stegner D, Popp M, Antkowiak A, Van Eeuwijk JMM, Nurden P, Stritt S, Heib T, Aurbach K, Angay O, Cherpokova D, Heinz N, Baig AA, Gorelashvili MG, Gerner F, Heinze KG, Ware J, Krohne G, Ruggeri ZM, Nurden AT, Schulze H, Modlich U, Pleines I, Brakebusch C, Nieswandt B (2017)
Publication Type: Journal article
Publication year: 2017
Journal
Book Volume: 8
Article Number: 15838
DOI: 10.1038/ncomms15838
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.
Involved external institutions
Universitätsklinikum Heidelberg
Germany (DE)
Université Fédérale de Toulouse Midi-Pyrénées
France (FR)
Julius-Maximilians-Universität Würzburg
Germany (DE)
LOEWE Center for Cell and Gene Therapy (CGT)
Germany (DE)
University of Arkansas
United States (USA) (US)
Scripps Research Institute (TSRI)
United States (USA) (US)
Hôpital Xavier Arnozan
France (FR)
University of Copenhagen
Denmark (DK)
Germany (DE)
Université Fédérale de Toulouse Midi-Pyrénées
France (FR)
Julius-Maximilians-Universität Würzburg
Germany (DE)
LOEWE Center for Cell and Gene Therapy (CGT)
Germany (DE)
University of Arkansas
United States (USA) (US)
Scripps Research Institute (TSRI)
United States (USA) (US)
Hôpital Xavier Arnozan
France (FR)
University of Copenhagen
Denmark (DK)
How to cite
APA:
Duetting, S., Gaits-Iacovoni, F., Stegner, D., Popp, M., Antkowiak, A., Van Eeuwijk, J.M.M.,... Nieswandt, B. (2017). A Cdc42/RhoA regulatory circuit downstream of glycoprotein Ib guides transendothelial platelet biogenesis. Nature Communications, 8. https://doi.org/10.1038/ncomms15838
MLA:
Duetting, Sebastian, et al. "A Cdc42/RhoA regulatory circuit downstream of glycoprotein Ib guides transendothelial platelet biogenesis." Nature Communications 8 (2017).
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