TY - JOUR
T1 - Defects in TRPM7 channel function deregulate thrombopoiesis through altered cellular Mg 2+ homeostasis and cytoskeletal architecture
AU - Stritt, Simon
AU - Nurden, Paquita
AU - Favier, Remi
AU - Favier, Marie
AU - Ferioli, Silvia
AU - Gotru, Sanjeev K.
AU - Van Eeuwijk, Judith M.M.
AU - Schulze, Harald
AU - Nurden, Alan T.
AU - Lambert, Michele P.
AU - Turro, Ernest
AU - Burger-Stritt, Stephanie
AU - Matsushita, Masayuki
AU - Mittermeier, Lorenz
AU - Ballerini, Paola
AU - Zierler, Susanna
AU - Laffan, Michael A.
AU - Chubanov, Vladimir
AU - Gudermann, Thomas
AU - Nieswandt, Bernhard
AU - Braun, Attila
N1 - Funding Information:
We thank the microscopy platform of the Bioimaging Centre (Rudolf Virchow Centre) for providing technical infrastructure and support. This work was supported by the Deutsche Forschungsgemeinschaft (SFB 688 to H.S., B.N. and A.B.). S.S. and J.M.M.v.E. were supported by a grant of the German Excellence Initiative to the Graduate School of Life Sciences, University of Würzburg. V.C., S.Z. and T.G. were supported by the Deutsche Forschungsgemeinschaft, TRR 152. Research in the Ouwehand laboratory was supported by programme grants from the European Commission, NIHR and the BHF under numbers RP-PG-0310-1002 and RG/09/12/28096 and the laboratory also receives funding from NHS Blood and Transplant. M.A.L. was supported by the Imperial College London Biomedical Research Centre.
PY - 2016/3/29
Y1 - 2016/3/29
N2 - Mg2+ plays a vital role in platelet function, but despite implications for life-threatening conditions such as stroke or myocardial infarction, the mechanisms controlling [Mg2+] i in megakaryocytes (MKs) and platelets are largely unknown. Transient receptor potential melastatin-like 7 channel (TRPM7) is a ubiquitous, constitutively active cation channel with a cytosolic α-kinase domain that is critical for embryonic development and cell survival. Here we report that impaired channel function of TRPM7 in MKs causes macrothrombocytopenia in mice (Trpm7 fl/fl-Pf4Cre) and likely in several members of a human pedigree that, in addition, suffer from atrial fibrillation. The defect in platelet biogenesis is mainly caused by cytoskeletal alterations resulting in impaired proplatelet formation by Trpm7 fl/fl-Pf4Cre MKs, which is rescued by Mg2+ supplementation or chemical inhibition of non-muscle myosin IIA heavy chain activity. Collectively, our findings reveal that TRPM7 dysfunction may cause macrothrombocytopenia in humans and mice.
AB - Mg2+ plays a vital role in platelet function, but despite implications for life-threatening conditions such as stroke or myocardial infarction, the mechanisms controlling [Mg2+] i in megakaryocytes (MKs) and platelets are largely unknown. Transient receptor potential melastatin-like 7 channel (TRPM7) is a ubiquitous, constitutively active cation channel with a cytosolic α-kinase domain that is critical for embryonic development and cell survival. Here we report that impaired channel function of TRPM7 in MKs causes macrothrombocytopenia in mice (Trpm7 fl/fl-Pf4Cre) and likely in several members of a human pedigree that, in addition, suffer from atrial fibrillation. The defect in platelet biogenesis is mainly caused by cytoskeletal alterations resulting in impaired proplatelet formation by Trpm7 fl/fl-Pf4Cre MKs, which is rescued by Mg2+ supplementation or chemical inhibition of non-muscle myosin IIA heavy chain activity. Collectively, our findings reveal that TRPM7 dysfunction may cause macrothrombocytopenia in humans and mice.
UR - http://www.scopus.com/inward/record.url?scp=84962637978&partnerID=8YFLogxK
U2 - 10.1038/ncomms11097
DO - 10.1038/ncomms11097
M3 - Article
C2 - 27020697
AN - SCOPUS:84962637978
SN - 2041-1723
VL - 7
JO - Nature Communications
JF - Nature Communications
M1 - 11097
ER -