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Nat Commun. 2017 Jun 15;8:15838. doi: 10.1038/ncomms15838.

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

Author information

1
Institute of Experimental Biomedicine, University Hospital and University of Würzburg, Josef-Schneider-Str. 2, 97080 Würzburg, Germany.
2
Rudolf Virchow Center, University of Würzburg, Josef-Schneider-Str. 2, 97080 Würzburg, Germany.
3
INSERM UMR1048, Institut des Maladies Métaboliques et Cardiovasculaires-I2MC, UMR1048, Institut National de la Santé et de la Recherche Médicale, Université de Toulouse, 1 Avenue Jean Poulhès, BP 84225, 31432 Toulouse Cedex 4, France.
4
Institut Hospitalo-Universitaire LIRYC, Plateforme Technologique d'Innovation Biomédicale, Hôpital Xavier Arnozan, Avenue du Haut Lévêque, 33604 Pessac, France.
5
Research Group for Gene Modification in Stem Cells, LOEWE Center for Cell and Gene Therapy Frankfurt/Main and the Paul-Ehrlich-Institute, Paul-Ehrlich-Straße 51-59, 63225 Langen, Germany.
6
Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, Arkansass 72205, USA.
7
Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
8
Department of Molecular Medicine, The Scripps Research Institute, 10550 N Torrey Pines Rd, La Jolla, California 92037, USA.
9
BRIC, Biomedical Institute, University of Copenhagen, Nørregade 10, 1165 Copenhagen, Denmark.

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.

PMID:
28643773
PMCID:
PMC5481742
DOI:
10.1038/ncomms15838
[Indexed for MEDLINE]
Free PMC Article

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