title: Dynamin 2-dependent endocytosis is required for normal megakaryocyte development in mice.
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.
authors.affiliation: Division of Hematology, Brigham and Women's Hospital, Boston, MA; Department of Medicine, Harvard Medical School, Boston, MA;
authors.forename: Markus
authors.initials: M
authors.lastname: Bender
authors.affiliation: Division of Hematology, Brigham and Women's Hospital, Boston, MA; Department of Medicine, Harvard Medical School, Boston, MA;
authors.forename: Silvia
authors.initials: S
authors.lastname: Giannini
authors.affiliation: Division of Hematology, Brigham and Women's Hospital, Boston, MA; Department of Medicine, Harvard Medical School, Boston, MA;
authors.forename: Renata
authors.initials: R
authors.lastname: Grozovsky
authors.affiliation: Division of Hematology, Brigham and Women's Hospital, Boston, MA; Department of Medicine, Harvard Medical School, Boston, MA; Department of Medical Chemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden;
authors.forename: Terese
authors.initials: T
authors.lastname: Jönsson
authors.affiliation: Program in Cell Biology, The Hospital for Sick Children, Toronto, ON, Canada; and.
authors.forename: Hilary
authors.initials: H
authors.lastname: Christensen
authors.affiliation: Program in Cell Biology, The Hospital for Sick Children, Toronto, ON, Canada; and.
authors.forename: Fred G
authors.initials: FG
authors.lastname: Pluthero
authors.affiliation: Division of Hematology, Brigham and Women's Hospital, Boston, MA; Department of Medicine, Harvard Medical School, Boston, MA;
authors.forename: Amy
authors.initials: A
authors.lastname: Ko
authors.affiliation: Division of Hematology, Brigham and Women's Hospital, Boston, MA; Department of Medicine, Harvard Medical School, Boston, MA;
authors.forename: Ann
authors.initials: A
authors.lastname: Mullally
authors.affiliation: Program in Cell Biology, The Hospital for Sick Children, Toronto, ON, Canada; and Department of Pediatrics and Department of Biochemistry, University of Toronto, Toronto, ON, Canada.
authors.forename: Walter H A
authors.initials: WH
authors.lastname: Kahr
authors.affiliation: Division of Hematology, Brigham and Women's Hospital, Boston, MA; Department of Medicine, Harvard Medical School, Boston, MA;
authors.forename: Karin M
authors.initials: KM
authors.lastname: Hoffmeister
authors.affiliation: Division of Hematology, Brigham and Women's Hospital, Boston, MA; Department of Medicine, Harvard Medical School, Boston, MA;
authors.forename: Hervé
authors.initials: H
authors.lastname: Falet
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D034285:Dynamin II / Q000235:genetics / Q000378:metabolism*; D004705:Endocytosis; D017353:Gene Deletion; D008533:Megakaryocytes / Q000166:cytology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D053628:Receptors, Thrombopoietin / Q000378:metabolism; D015398:Signal Transduction; D013163:Splenomegaly / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D013921:Thrombocytopenia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D034061:Thrombopoiesis
chemical_list: C481270:Mpl protein, mouse; D053628:Receptors, Thrombopoietin; D034285:Dynamin II