STAT1 promotes megakaryopoiesis downstream of GATA-1 in mice.
Thrombocytosis is associated with inflammation, and certain inflammatory cytokines, including IFN-gamma, stimulate megakaryocyte and platelet production. However, the roles of IFN-gamma and its downstream effector STAT1 in megakaryocyte development are poorly understood. We previously reported that STAT1 expression was significantly downregulated in Gata1-knockdown murine megakaryocytes, which also have impaired terminal maturation. Here, we show that ectopic expression of STAT1, or its target effector IRF-1, rescued multiple defects in Gata1-deficient megakaryopoiesis in mice, inducing polyploidization and expression of a subset of platelet-expressing genes. Enforced expression of STAT1, IRF-1, or GATA-1 enhanced phosphorylation of STAT1, STAT3, and STAT5 in cultured Gata1-deficient murine megakaryocytes, with concomitant megakaryocyte maturation. In contrast, enhanced thrombopoietin signaling, conferred by enforced expression of constitutively active JAK2 or c-MPL, induced phosphorylation of STAT3 and STAT5, but not STAT1, and failed to rescue megakaryocyte maturation. Finally, megakaryocytes from Stat1(-/-) mice were defective in polyploidization. Together, these findings reveal a unique role for STAT1 in megakaryopoiesis and provide new insights into how GATA-1 regulates this process. Our studies elucidate potential mechanisms by which various inflammatory disorders can cause elevated platelet counts.
Department of Medicine, Division of Hematology and Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
Zan
Z
Huang
Terri D
TD
Richmond
Andrew G
AG
Muntean
Dwayne L
DL
Barber
Mitchell J
MJ
Weiss
John D
JD
Crispino
D000818:Animals; D001792:Blood Platelets / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D050982:GATA1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D050856:Interferon Regulatory Factor-1 / Q000235:genetics / Q000378:metabolism; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D008533:Megakaryocytes / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D010976:Platelet Count; D011003:Ploidies; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism; D013922:Thrombocytosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D034061:Thrombopoiesis / Q000235:genetics
D050982:GATA1 Transcription Factor; C494689:Gata1 protein, mouse; D050856:Interferon Regulatory Factor-1; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; D007371:Interferon-gamma