Consequences of GATA-1 deficiency in megakaryocytes and platelets

In the absence of the hematopoietic transcription factor GATA-1, mice devel op thrombocytopenia and an increased number of megakaryocytes characterized by marked ultrastructural abnormalities. These observations establish a cr itical role for GATA-1 in megakaryopoiesis and raise the question as to how GATA-1 influences megakaryocyte maturation and platelet production. To beg in to address this, we have performed a more detailed examination of the me gakaryocytes and platelets produced in mice that lack GATA-1 in this lineag e. Our analysis demonstrates that compared with their normal counterparts, GATA-1-deficient primary megakaryocytes exhibit significant hyperproliferat ion 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 significa nt proportion of these cells do not undergo endomitosis and express markedl y lower levels of mRNA of all megakaryocyte-associated genes tested, includ ing GPIb alpha, GPIb beta, platelet factor 4 (PF4), c-mpl, and p45 NF-EP. T hese results are consistent with regulation of a program of megakaryocytic differentiation by GATA-1. Bleeding times are significantly prolonged in mu tant animals. GATA-1-deficient platelets show abnormal ultrastructure, remi niscent of the megakaryocytes from which they are derived, and exhibit mode st but selective defects in platelet activation in response to thrombin or to the combination of adenosine diphosphate (ADP) and epinephrine, Our find ings indicate that GATA-1 serves multiple functions in megakaryocyte develo pment, influencing both cellular growth and maturation. (C) 1999 by The Ame rican Society of Hematology.