Cellular and molecular biology of megakaryocyte differentiation in the absence of lineage-restricted transcription factors.
Targeted gene disruption of two distinct lineage-restricted hematopoietic transcription factors has provided useful insights into the transcriptional control of platelet production. Absence of either the basic leucine-zipper protein NF-E2 or of the zinc-finger protein GATA-1 in vivo results in severe thrombocytopenia secondary to distinct patterns of arrested megakaryocyte cytoplasmic maturation; in addition, megakaryocyte-selective loss of GATA-1 expression leads to dysregulated proliferation of progenitor cells. The ultrastructure of the defective megakaryocytes suggests that absence of the respective transcription factors impairs biogenesis of platelet-specific granules and proper development and organization of demarcation membranes. In particular, transcriptional targets of NF-E2 may be implicated in the very final stages of megakaryocyte differentiation, which involve the organization and release of platelets. Preliminary characterization of genes that are downregulated in NF-E2-/- megakaryocytes is in progress and is likely to lead to mechanistic insights into thrombocytopoiesis.
Lecine
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Departments of Medicine, The Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA.
Shivdasani
R A
RA
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D019070:Cell Lineage / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D050981:Erythroid-Specific DNA-Binding Factors; D050982:GATA1 Transcription Factor; D008533:Megakaryocytes / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D016297:Mutagenesis, Site-Directed / Q000502:physiology; D050983:NF-E2 Transcription Factor; D050984:NF-E2 Transcription Factor, p45 Subunit; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics*
D004268:DNA-Binding Proteins; D050981:Erythroid-Specific DNA-Binding Factors; D050982:GATA1 Transcription Factor; C494689:Gata1 protein, mouse; D050983:NF-E2 Transcription Factor; D050984:NF-E2 Transcription Factor, p45 Subunit; C494693:Nfe2 protein, mouse; D014157:Transcription Factors