title: Shaping of terminal megakaryocyte differentiation and proplatelet development by sphingosine-1-phosphate receptor S1P4.
abstract: Megakaryocytes, which mature from hematopoietic progenitors in the bone marrow, further differentiate by reorganizing their cytoplasm into long proplatelet extensions that release platelets into the circulation. The molecular mechanisms underlying this highly dynamic cytoplasmic and cytoskeletal remodeling process are only poorly understood. Here we report that sphingosine 1-phosphate receptor 4 (S1P(4)) is specifically up-regulated during the development of human megakaryocytes from progenitor cells and is expressed in mature murine megakaryocytes. Megakaryocytes generated from S1P(4)-deficient murine bone marrow showed atypical and reduced formation of proplatelets in vitro. The recovery of platelet numbers after experimental thrombocytopenia was significantly delayed in S1p4(-/-) mice. Remarkably, overexpression and stimulation of S1P(4) in human erythroleukemia HEL cells promoted endomitosis, formation of cytoplasmic extensions, and subsequent release of platelet-like particles. These observations indicate that S1P(4) is involved in shaping the terminal differentiation of megakaryocytes.
authors.affiliation: Department of Tumor Genetics and Immunogenetics, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Golfier
authors.forename: Shinichi
authors.initials: S
authors.lastname: Kondo
authors.forename: Tobias
authors.initials: T
authors.lastname: Schulze
authors.forename: Tomomi
authors.initials: T
authors.lastname: Takeuchi
authors.forename: Galya
authors.initials: G
authors.lastname: Vassileva
authors.forename: Ariel H
authors.initials: AH
authors.lastname: Achtman
authors.forename: Markus H
authors.initials: MH
authors.lastname: Gräler
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Abbondanzo
authors.forename: Maria
authors.initials: M
authors.lastname: Wiekowski
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Kremmer
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Endo
authors.forename: Sergio A
authors.initials: SA
authors.lastname: Lira
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Bacon
authors.forename: Martin
authors.initials: M
authors.lastname: Lipp
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000166:cytology*; D015139:Blotting, Southern; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000166:cytology; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D008297:Male; D008533:Megakaryocytes / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D040201:Platelet Membrane Glycoprotein IIb / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013921:Thrombocytopenia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D013926:Thrombopoietin / Q000097:blood
chemical_list: D040201:Platelet Membrane Glycoprotein IIb; D049349:Receptors, Lysosphingolipid; D013926:Thrombopoietin