Deregulation of thrombopoiesis from defects in TRPM7 channel function

Deregulation of thrombopoiesis from defects in TRPM7 channel function

Platelets are continuously produced from megakaryocytes (MKs) in the bone marrow by a cytoskeleton-driven process of which the molecular regulation is not fully understood. MKs extend long cytoplasmic protrusions into bone marrow sinusoids, where larger fragments, so-called preplatelets, are shed and further divide within the circulation to give rise to platelets.

Transient receptor potential melastatin-like 7 (TRPM7) channel and kinase domain, but not its kinase activity, are critical for embryonic development and knockdown or cell-specific TRPM7 knockout approaches give rise to impaired cytoskeletal organization, cell migration, proliferation, polarization and survival. TRPM7 has been implicated as a key regulator of signal conductance in the murine heart by regulating the expression of different pacemaker channels, such as HCN4. Although TRPM7-mediated cation influx has been detected in MKs, its role in thrombopoiesis has not been investigated to date.

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.

Researchers report that impaired channel function but not kinase activity of TRPM7 in MKs causes macrothrombocytopenia in Trpm7fl/fl-Pf4Cre mice and likely in several members of a human pedigree, which, in addition, feature atrial fibrillation.

The impaired proplatelet formation is associated with cytoskeletal alterations due to increased actomyosin contractility and can be rescued by either Mg2+ supplementation or chemical inhibition of NMMIIA activity.

Collectively, these findings reveal TRPM7 dysfunction as a novel cause of macrothrombocytopenia in mice and potentially in humans too.

http://www.nature.com/ncomms/2016/160329/ncomms11097/full/ncomms11097.html

Edited

Rating

Unrated
Rating: