Thrombocytopenia in Mice Lacking the Carboxy-Terminal Regulatory Domain of the Ets Transcription Factor Fli1

Abstract

ABSTRACTTargeted disruption of theFli1gene results in embryonic lethality. To dissect the roles of functional domains in Fli1, we recently generated mutantFli1mice that express a truncated Fli1 protein (Fli1ΔCTA) that lacks the carboxy-terminal regulatory (CTA) domain. HeterozygousFli1ΔCTAmice are viable, while homozygous mice have reduced viability. Early postnatal lethality accounts for 30% survival of homozygotes to adulthood. The peripheral blood of these viableFli1ΔCTA/Fli1ΔCTAhomozygous mice has reduced platelet numbers. Platelet aggregation and activation were also impaired and bleeding times significantly prolonged in these mutant mice. Analysis of mRNA from total bone marrow and purified megakaryocytes fromFli1ΔCTA/Fli1ΔCTAmice revealed downregulation of genes associated with megakaroyctic development, includingc-mpl,gpIIb,gpIV,gpIX,PF4,NF-E2,MafG, andRab27B. While Fli1 and GATA-1 synergistically regulate the expression of multiple megakaryocytic genes, the level of GATA-1 present on a subset of these promoters is reducedin vivoin theFli1ΔCTA/Fli1ΔCTAmice, providing a possible mechanism for the impared transcription observed. Collectively, these data showed for the first time a hemostatic defect associated with the loss of a specific functional domain of the transcription factor Fli1 and suggest previously unknownin vivoroles in megakaryocytic cell differentiation.