title: A novel role of sphingosine 1-phosphate receptor S1pr1 in mouse thrombopoiesis.
abstract: Millions of platelets are produced each hour by bone marrow (BM) megakaryocytes (MKs). MKs extend transendothelial proplatelet (PP) extensions into BM sinusoids and shed new platelets into the blood. The mechanisms that control platelet generation remain incompletely understood. Using conditional mutants and intravital multiphoton microscopy, we show here that the lipid mediator sphingosine 1-phosphate (S1P) serves as a critical directional cue guiding the elongation of megakaryocytic PP extensions from the interstitium into BM sinusoids and triggering the subsequent shedding of PPs into the blood. Correspondingly, mice lacking the S1P receptor S1pr1 develop severe thrombocytopenia caused by both formation of aberrant extravascular PPs and defective intravascular PP shedding. In contrast, activation of S1pr1 signaling leads to the prompt release of new platelets into the circulating blood. Collectively, our findings uncover a novel function of the S1P-S1pr1 axis as master regulator of efficient thrombopoiesis and might raise new therapeutic options for patients with thrombocytopenia.
authors.affiliation: Medizinische Klinik und Poliklinik I, Klinikum der Universität, Ludwig-Maximilian-Universität München, 81337 Munich, Germany.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.forename: Martin
authors.initials: M
authors.lastname: Orban
authors.forename: Michael
authors.initials: M
authors.lastname: Lorenz
authors.forename: Verena
authors.initials: V
authors.lastname: Barocke
authors.forename: Daniel
authors.initials: D
authors.lastname: Braun
authors.forename: Nicole
authors.initials: N
authors.lastname: Urtz
authors.forename: Christian
authors.initials: C
authors.lastname: Schulz
authors.forename: Marie-Luise
authors.initials: ML
authors.lastname: von Brühl
authors.forename: Anca
authors.initials: A
authors.lastname: Tirniceriu
authors.forename: Florian
authors.initials: F
authors.lastname: Gaertner
authors.forename: Richard L
authors.initials: RL
authors.lastname: Proia
authors.forename: Thomas
authors.initials: T
authors.lastname: Graf
authors.forename: Steffen-Sebastian
authors.initials: SS
authors.lastname: Bolz
authors.forename: Eloi
authors.initials: E
authors.lastname: Montanez
authors.forename: Marco
authors.initials: M
authors.lastname: Prinz
authors.forename: Alexandra
authors.initials: A
authors.lastname: Müller
authors.forename: Louisa
authors.initials: L
authors.lastname: von Baumgarten
authors.forename: Andreas
authors.initials: A
authors.lastname: Billich
authors.forename: Michael
authors.initials: M
authors.lastname: Sixt
authors.forename: Reinhard
authors.initials: R
authors.lastname: Fässler
authors.forename: Ulrich H
authors.initials: UH
authors.lastname: von Andrian
authors.forename: Tobias
authors.initials: T
authors.lastname: Junt
authors.forename: Steffen
authors.initials: S
authors.lastname: Massberg
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000502:physiology; D015153:Blotting, Western; D022081:Cell Surface Extensions / Q000502:physiology; D002478:Cells, Cultured; D005434:Flow Cytometry; D008246:Lysophospholipids / Q000378:metabolism*; D008533:Megakaryocytes / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D049349:Receptors, Lysosphingolipid / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D000081025:Sphingosine-1-Phosphate Receptors; D018709:Statistics, Nonparametric; D013921:Thrombocytopenia / Q000378:metabolism*; D034061:Thrombopoiesis / Q000235:genetics / Q000502:physiology*
chemical_list: D008246:Lysophospholipids; D049349:Receptors, Lysosphingolipid; C556330:S1pr1 protein, mouse; D000081025:Sphingosine-1-Phosphate Receptors; C060506:sphingosine 1-phosphate; D013110:Sphingosine