Thrombocytopenia in mice lacking the carboxy-terminal regulatory domain of the Ets transcription factor Fli1.
Targeted disruption of the Fli1 gene results in embryonic lethality. To dissect the roles of functional domains in Fli1, we recently generated mutant Fli1 mice that express a truncated Fli1 protein (Fli1(ΔCTA)) that lacks the carboxy-terminal regulatory (CTA) domain. Heterozygous Fli1(ΔCTA) mice are viable, while homozygous mice have reduced viability. Early postnatal lethality accounts for 30% survival of homozygotes to adulthood. The peripheral blood of these viable Fli1(ΔCTA)/Fli1(ΔCTA) homozygous 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 from Fli1(ΔCTA)/Fli1(ΔCTA) mice revealed downregulation of genes associated with megakaroyctic development, including c-mpl, gpIIb, gpIV, gpIX, PF4, NF-E2, MafG, and Rab27B. 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 reduced in vivo in the Fli1(ΔCTA)/Fli1(ΔCTA) mice, 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 unknown in vivo roles in megakaryocytic cell differentiation.
Moussa
Omar
O
Department of Pathology and Laboratory Medicine, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA.
LaRue
Amanda C
AC
Abangan
Romeo S
RS
Williams
Christopher R
CR
Zhang
Xian K
XK
Masuya
Masahiro
M
Gong
Yong Z
YZ
Spyropoulos
Demetri D
DD
Ogawa
Makio
M
Gilkeson
Gary
G
Watson
Dennis K
DK
D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D017931:DNA Primers / Q000235:genetics; D005260:Female; D050982:GATA1 Transcription Factor / Q000378:metabolism; D006367:HeLa Cells; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D008533:Megakaryocytes / Q000166:cytology / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D015539:Platelet Activation; D010976:Platelet Count; D011247:Pregnancy; D017434:Protein Structure, Tertiary; D051789:Proto-Oncogene Protein c-fli-1 / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D013921:Thrombocytopenia / Q000097:blood / Q000209:etiology* / Q000235:genetics; D014162:Transfection
D017931:DNA Primers; C497426:Fli1 protein, mouse; D050982:GATA1 Transcription Factor; C494689:Gata1 protein, mouse; D050505:Mutant Proteins; D010446:Peptide Fragments; D051789:Proto-Oncogene Protein c-fli-1
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