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Dynamin 2-dependent endocytosis is required for normal megakaryocyte development in mice. Blood 2015 Feb 05;125(6):1014-24

Date

12/04/2014

Pubmed ID

25468568

Pubmed Central ID

PMC4319232

DOI

10.1182/blood-2014-07-587857

Scopus ID

2-s2.0-84922341743 (requires institutional sign-in at Scopus site)   45 Citations

Abstract

Dynamins are highly conserved large GTPases (enzymes that hydrolyze guanosine triphosphate) involved in endocytosis and vesicle transport, and mutations in the ubiquitous and housekeeping dynamin 2 (DNM2) have been associated with thrombocytopenia in humans. To determine the role of DNM2 in thrombopoiesis, we generated Dnm2(fl/fl) Pf4-Cre mice specifically lacking DNM2 in the megakaryocyte (MK) lineage. Dnm2(fl/fl) Pf4-Cre mice had severe macrothrombocytopenia with moderately accelerated platelet clearance. Dnm2-null bone marrow MKs had altered demarcation membrane system formation in vivo due to defective endocytic pathway, and fetal liver-derived Dnm2-null MKs formed proplatelets poorly in vitro, showing that DNM2-dependent endocytosis plays a major role in MK membrane formation and thrombopoiesis. Endocytosis of the thrombopoietin receptor Mpl was impaired in Dnm2-null platelets, causing constitutive phosphorylation of the tyrosine kinase JAK2 and elevated circulating thrombopoietin levels. MK-specific DNM2 deletion severely disrupted bone marrow homeostasis, as reflected by marked expansion of hematopoietic stem and progenitor cells, MK hyperplasia, myelofibrosis, and consequent extramedullary hematopoiesis and splenomegaly. Taken together, our data demonstrate that unrestrained MK growth and proliferation results in rapid myelofibrosis and establishes a previously unrecognized role for DNM2-dependent endocytosis in megakaryopoiesis, thrombopoiesis, and bone marrow homeostasis.

Author List

Bender M, Giannini S, Grozovsky R, Jönsson T, Christensen H, Pluthero FG, Ko A, Mullally A, Kahr WH, Hoffmeister KM, Falet H

Authors

Herve Falet PhD Associate Professor in the Cell Biology Neurobiology and Anatomy department at Medical College of Wisconsin
Karin Hoffmeister MD Professor in the Biochemistry department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Blood Platelets
Bone Marrow
Dynamin II
Endocytosis
Gene Deletion
Megakaryocytes
Mice
Mice, Inbred C57BL
Receptors, Thrombopoietin
Signal Transduction
Splenomegaly
Thrombocytopenia
Thrombopoiesis