Consequences of GATA-1 deficiency in megakaryocytes and platelets.
In the absence of the hematopoietic transcription factor GATA-1, mice develop thrombocytopenia and an increased number of megakaryocytes characterized by marked ultrastructural abnormalities. These observations establish a critical role for GATA-1 in megakaryopoiesis and raise the question as to how GATA-1 influences megakaryocyte maturation and platelet production. To begin to address this, we have performed a more detailed examination of the megakaryocytes and platelets produced in mice that lack GATA-1 in this lineage. Our analysis demonstrates that compared with their normal counterparts, GATA-1-deficient primary megakaryocytes exhibit significant hyperproliferation in liquid culture, suggesting that the megakaryocytosis seen in animals is nonreactive. Morphologically, these mutant megakaryocytes are small and show evidence of retarded nuclear and cytoplasmic development. A significant proportion of these cells do not undergo endomitosis and express markedly lower levels of mRNA of all megakaryocyte-associated genes tested, including GPIbalpha, GPIbbeta, platelet factor 4 (PF4), c-mpl, and p45 NF-E2. These results are consistent with regulation of a program of megakaryocytic differentiation by GATA-1. Bleeding times are significantly prolonged in mutant animals. GATA-1-deficient platelets show abnormal ultrastructure, reminiscent of the megakaryocytes from which they are derived, and exhibit modest but selective defects in platelet activation in response to thrombin or to the combination of adenosine diphosphate (ADP) and epinephrine. Our findings indicate that GATA-1 serves multiple functions in megakaryocyte development, influencing both cellular growth and maturation.
Vyas
P
P
Department of Hematology-Oncology and Howard Hughes Medical Institute, Children's Hospital, Boston, MA, USA. vyas@rascal.med.harvard.edu
Ault
K
K
Jackson
C W
CW
Orkin
S H
SH
Shivdasani
R A
RA
D000818:Animals; D001792:Blood Platelets / Q000166:cytology / Q000502:physiology*; D002455:Cell Division; D004268:DNA-Binding Proteins / Q000097:blood* / Q000235:genetics*; D050981:Erythroid-Specific DNA-Binding Factors; D050982:GATA1 Transcription Factor; D005786:Gene Expression Regulation; D007700:Kinetics; D008533:Megakaryocytes / Q000166:cytology / Q000502:physiology* / Q000648:ultrastructure; D051379:Mice; D018345:Mice, Knockout; D008938:Mitosis; D050983:NF-E2 Transcription Factor; D050984:NF-E2 Transcription Factor, p45 Subunit; D009363:Neoplasm Proteins; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics; D010978:Platelet Factor 4 / Q000235:genetics; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D018121:Receptors, Cytokine; D053628:Receptors, Thrombopoietin; D013921:Thrombocytopenia / Q000097:blood / Q000235:genetics; D014157:Transcription Factors / Q000097:blood* / Q000235:genetics*; D014158:Transcription, Genetic
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; D009363:Neoplasm Proteins; C494693:Nfe2 protein, mouse; D009687:Nuclear Proteins; D019038:Platelet Glycoprotein GPIb-IX Complex; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D018121:Receptors, Cytokine; D053628:Receptors, Thrombopoietin; D014157:Transcription Factors; C082218:MPL protein, human; D010978:Platelet Factor 4