Normal hemostasis but defective hematopoietic response to growth factors in mice deficient in phospholipid scramblase 1.
Phospholipid scramblase 1 (PLSCR1) is an endofacial plasma membrane protein proposed to participate in transbilayer movement of phosphatidylserine and other phospholipids. In addition to its putative role in the reorganization of plasma membrane phospholipids, PLSCR1 is a substrate of intracellular kinases that imply its possible participation in diverse signaling pathways underlying proliferation, differentiation, or apoptosis. Because PLSCR1 is prominently expressed in a variety of blood cells, we evaluated PLSCR activity in platelets and erythrocytes, and cytokine-dependent growth of hematopoietic precursor cells, of PLSCR1 knock-out mice. Adult PLSCR1(-/-) mice showed no obvious hematologic or hemostatic abnormality, and blood cells from these animals normally mobilized phosphatidylserine to the cell surface upon stimulation. Whereas blood cell counts in adult PLSCR1(-/-) mice were normal, in both fetus and newborn animals neutrophil counts were significantly depressed relative to age-matched wild type (WT). Furthermore, when compared with WT, hematopoietic precursor cells from PLSCR1(-/-) mice showed defective colony formation and impaired differentiation to mature granulocytes as stimulated by stem cell factor and granulocyte colony-stimulating factor (G-CSF). By contrast, PLSCR1(-/-) cells showed normal colony formation stimulated by interleukin-3 or granulocyte-macrophage CSF, and expansion of megakaryocytic and erythroid progenitors by thrombopoietin or erythropoietin was unaffected. Stem cell factor and G-CSF were also found to induce marked increases in PLSCR1 levels in WT cells. Consistent with in vitro assays, PLSCR1(-/-) mice treated with G-CSF showed less than 50% of the granulocytosis observed in identically treated WT mice. These data provide direct evidence that PLSCR1 functionally contributes to cytokine-regulated cell proliferation and differentiation and suggest it is required for normal myelopoiesis.
Zhou
Quansheng
Q
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
Zhao
Ji
J
Wiedmer
Therese
T
Sims
Peter J
PJ
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D001760:Bleeding Time; D001792:Blood Platelets / Q000502:physiology*; D001854:Bone Marrow Cells / Q000166:cytology; D017301:Ca(2+) Mg(2+)-ATPase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D005333:Fetus; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006098:Granulocytes / Q000502:physiology; D006133:Growth Substances / Q000494:pharmacology*; D006410:Hematopoiesis / Q000187:drug effects / Q000502:physiology*; D006487:Hemostasis / Q000502:physiology*; D008099:Liver / Q000166:cytology / Q000502:physiology; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D049294:Phospholipid Transfer Proteins; D015539:Platelet Activation; D012016:Reference Values; D019089:Stem Cell Factor / Q000494:pharmacology
D002352:Carrier Proteins; D006133:Growth Substances; D008565:Membrane Proteins; D049294:Phospholipid Transfer Proteins; D019089:Stem Cell Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D017301:Ca(2+) Mg(2+)-ATPase