The May-Hegglin anomaly gene MYH9 is a negative regulator of platelet biogenesis modulated by the Rho-ROCK pathway

Blood. 2007 Jul 1;110(1):171-9. doi: 10.1182/blood-2007-02-071589. Epub 2007 Mar 28.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Platelets / cytology*
  • Embryonic Stem Cells / cytology
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Megakaryocytes / cytology
  • Mice
  • Myosin Light Chains / metabolism
  • Nonmuscle Myosin Type IIA / genetics
  • Nonmuscle Myosin Type IIA / physiology*
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / metabolism*
  • Thrombopoiesis*
  • rho-Associated Kinases

Substances

  • Intracellular Signaling Peptides and Proteins
  • Myosin Light Chains
  • Protein-Serine-Threonine Kinases
  • rho-Associated Kinases
  • Nonmuscle Myosin Type IIA