The May-Hegglin anomaly gene MYH9 is a negative regulator of platelet biogenesis modulated by the Rho-ROCK pathway. Blood 2007 Jul 01;110(1):171-9
Date
03/30/2007Pubmed ID
17392504Pubmed Central ID
PMC1896110DOI
10.1182/blood-2007-02-071589Scopus ID
2-s2.0-34347390082 (requires institutional sign-in at Scopus site) 134 CitationsAbstract
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.
Author List
Chen Z, Naveiras O, Balduini A, Mammoto A, Conti MA, Adelstein RS, Ingber D, Daley GQ, Shivdasani RAAuthor
Akiko Mammoto MD, PhD Associate Professor in the Pediatrics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsBlood Platelets
Embryonic Stem Cells
Humans
Intracellular Signaling Peptides and Proteins
Megakaryocytes
Mice
Myosin Light Chains
Nonmuscle Myosin Type IIA
Phosphorylation
Thrombopoiesis
rho-Associated Kinases