The May-Hegglin anomaly gene MYH9 is a negative regulator of platelet biogenesis modulated by the Rho-ROCK pathway.
The gene implicated in the May-Hegglin anomaly and related macrothrombocytopenias, MYH9, encodes myosin-IIA, a protein that enables morphogenesis in diverse cell types. Defective myosin-IIA complexes are presumed to perturb megakaryocyte (MK) differentiation or generation of proplatelets. We observed that Myh9(-/-) mouse embryonic stem (ES) cells differentiate into MKs that are fully capable of proplatelet formation (PPF). In contrast, elevation of myosin-IIA activity, by exogenous expression or by mimicking constitutive phosphorylation of its regulatory myosin light chain (MLC), significantly attenuates PPF. This effect occurs only in the presence of myosin-IIA and implies that myosin-IIA influences thrombopoiesis negatively. MLC phosphorylation in MKs is regulated by Rho-associated kinase (ROCK), and consistent with our model, ROCK inhibition enhances PPF. Conversely, expression of AV14, a constitutive form of the ROCK activator Rho, blocks PPF, and this effect is rescued by simultaneous expression of a dominant inhibitory MLC form. Hematopoietic transplantation studies in mice confirm that interference with the putative Rho-ROCK-myosin-IIA pathway selectively decreases the number of circulating platelets. Our studies unveil a key regulatory pathway for platelet biogenesis and hint at Sdf-1/CXCL12 as one possible extracellular mediator. The unexpected mechanism for Myh9-associated thrombocytopenia may lead to new molecular approaches to manipulate thrombopoiesis.
Chen
Zhao
Z
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Naveiras
Olaia
O
Balduini
Alessandra
A
Mammoto
Akiko
A
Conti
Mary Anne
MA
Adelstein
Robert S
RS
Ingber
Donald
D
Daley
George Q
GQ
Shivdasani
Ramesh A
RA
D000818:Animals; D001792:Blood Platelets / Q000166:cytology*; D053595:Embryonic Stem Cells / Q000166:cytology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008533:Megakaryocytes / Q000166:cytology; D051379:Mice; D018994:Myosin Light Chains / Q000378:metabolism; D024507:Nonmuscle Myosin Type IIA / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D034061:Thrombopoiesis; D054460:rho-Associated Kinases
D047908:Intracellular Signaling Peptides and Proteins; D018994:Myosin Light Chains; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D024507:Nonmuscle Myosin Type IIA