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; Bernhard Nieswandt

doi:10.1038/ncomms15838

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. RuggeriAlan T. Nurden, Harald Schulze, Ute Modlich, Irina Pleines, Cord Brakebusch, Bernhard Nieswandt^*

^*Corresponding author af dette arbejde

Nutritional Immunology

29 Citationer (Scopus)

138 Downloads (Pure)

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.

Originalsprog	Engelsk
Artikelnummer	15838
Tidsskrift	Nature Communications
Vol/bind	8
Antal sider	13
ISSN	2041-1723
DOI	https://doi.org/10.1038/ncomms15838
Status	Udgivet - 15 jun. 2017

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10.1038/ncomms15838Licens: CC BY

A Cdc42/RhoA regulatory circuit downstream of glycoprotein Ib guides transendothelial platelet biogenesisForlagets udgivne version, 5,86 MBLicens: CC BY

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Dütting, S., Gaits-Iacovoni, F., Stegner, D., Popp, M., Antkowiak, A., Van Eeuwijk, J. M. M., Nurden, P., Stritt, S., Heib, T., Aurbach, K., Angay, O., Cherpokova, D., Heinz, N., Baig, A. A., Gorelashvili, M. G., Gerner, F., Heinze, K. G., Ware, J., Krohne, G., ... Nieswandt, B. (2017). A Cdc42/RhoA regulatory circuit downstream of glycoprotein Ib guides transendothelial platelet biogenesis. Nature Communications, 8, Artikel 15838. https://doi.org/10.1038/ncomms15838

Dütting, 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, 'A Cdc42/RhoA regulatory circuit downstream of glycoprotein Ib guides transendothelial platelet biogenesis', Nature Communications, bind 8, 15838. https://doi.org/10.1038/ncomms15838

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title = "A Cdc42/RhoA regulatory circuit downstream of glycoprotein Ib guides transendothelial platelet biogenesis",

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.",

author = "Sebastian D{\"u}tting and Frederique Gaits-Iacovoni and David Stegner and Michael Popp and Adrien Antkowiak and {Van Eeuwijk}, {Judith M.M.} and Paquita Nurden and Simon Stritt and Tobias Heib and Katja Aurbach and Oguzhan Angay and Deya Cherpokova and Niels Heinz and Baig, {Ayesha A.} and Gorelashvili, {Maximilian G.} and Frank Gerner and Heinze, {Katrin G.} and Jerry Ware and Georg Krohne and Ruggeri, {Zaverio M.} and Nurden, {Alan T.} and Harald Schulze and Ute Modlich and Irina Pleines and Cord Brakebusch and Bernhard Nieswandt",

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doi = "10.1038/ncomms15838",

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AU - Dütting, Sebastian

AU - Gaits-Iacovoni, Frederique

AU - Stegner, David

AU - Popp, Michael

AU - Antkowiak, Adrien

AU - Van Eeuwijk, Judith M.M.

AU - Nurden, Paquita

AU - Stritt, Simon

AU - Heib, Tobias

AU - Aurbach, Katja

AU - Angay, Oguzhan

AU - Cherpokova, Deya

AU - Heinz, Niels

AU - Baig, Ayesha A.

AU - Gorelashvili, Maximilian G.

AU - Gerner, Frank

AU - Heinze, Katrin G.

AU - Ware, Jerry

AU - Krohne, Georg

AU - Ruggeri, Zaverio M.

AU - Nurden, Alan T.

AU - Schulze, Harald

AU - Modlich, Ute

AU - Pleines, Irina

AU - Brakebusch, Cord

AU - Nieswandt, Bernhard

PY - 2017/6/15

Y1 - 2017/6/15

N2 - 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.

AB - 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.

U2 - 10.1038/ncomms15838

DO - 10.1038/ncomms15838

M3 - Journal article

C2 - 28643773

AN - SCOPUS:85020861204

SN - 2041-1723

VL - 8

JO - Nature Communications

JF - Nature Communications

M1 - 15838

ER -

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

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