A critical role for the transcription factor Scl in platelet production during stress thrombopoiesis.
The generation of platelets from megakaryocytes in the steady state is regulated by a variety of cytokines and transcription factors, including thrombopoietin (TPO), GATA-1, and NF-E2. Less is known about platelet production in the setting of stress thrombopoiesis, a pivotal event in the context of cytotoxic chemotherapy. Here we show in mice that the transcription factor Scl is critical for platelet production after chemotherapy and in thrombopoiesis induced by administration of TPO. Megakaryocytes from these mice showed appropriate increases in number and ploidy but failed to shed platelets. Ultrastructural examination of Scl-null megakaryocytes revealed a disorganized demarcation membrane and reduction in platelet granules. Quantitative real-time polymerase chain reaction showed that Scl-null platelets lacked NF-E2, and chromatin immunoprecipitation analysis demonstrated Scl binding to the NF-E2 promoter in the human megakaryoblastic-cell line Meg-01, along with its binding partners E47, Lmo2, and the cofactors Ldb1 and GATA-2. These findings suggest that Scl acts up-stream of NF-E2 expression to control megakaryocyte development and platelet release in settings of thrombopoietic stress.
McCormack
Matthew P
MP
Bone Marrow Research Laboratories, Royal Melbourne Hospital, Melbourne Health Research Directorate, c/o Royal Melbourne Hospital Post Office, Grattan St, Parkville VIC 3050 Australia.
Hall
Mark A
MA
Schoenwaelder
Simone M
SM
Zhao
Quan
Q
Ellis
Sarah
S
Prentice
Julia A
JA
Clarke
Ashleigh J
AJ
Slater
Nicholas J
NJ
Salmon
Jessica M
JM
Jackson
Shaun P
SP
Jane
Stephen M
SM
Curtis
David J
DJ
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism / Q000502:physiology*; D001792:Blood Platelets / Q000378:metabolism* / Q000502:physiology; D047369:Chromatin Immunoprecipitation; D006801:Humans; D008533:Megakaryocytes / Q000166:cytology / Q000648:ultrastructure; D051379:Mice; D050984:NF-E2 Transcription Factor, p45 Subunit / Q000378:metabolism; D010974:Platelet Aggregation; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000378:metabolism / Q000502:physiology*; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D013922:Thrombocytosis; D034061:Thrombopoiesis / Q000502:physiology*; D013926:Thrombopoietin / Q000378:metabolism
D051792:Basic Helix-Loop-Helix Proteins; D050984:NF-E2 Transcription Factor, p45 Subunit; D011518:Proto-Oncogene Proteins; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D013926:Thrombopoietin; C494693:Nfe2 protein, mouse; C489366:Tal1 protein, mouse