MICE LACKING TRANSCRIPTION FACTOR NF-E2 PROVIDE IN-VIVO VALIDATION OFTHE PROPLATELET MODEL OF THROMBOCYTOPOIESIS AND SHOW A PLATELET PRODUCTION DEFECT THAT IS INTRINSIC TO MEGAKARYOCYTES

Mechanisms of platelet production and release by mammalian megakaryocy tes are poorly understood. We used thrombocytopenic knockout mice to b etter understand these processes. Proplatelets are filamentous extensi ons of terminally differentiated megakaryocytes that are thought to re present one mechanism of platelet release; however, these structures h ave largely been recognized in cultured cells and there has been no co rrelation between thrombocytopoiesis in vivo and proplatelet formation . Mice lacking transcription factor NF-E2 have a late arrest in megaka ryocyte maturation, resulting in profound thrombocytopenia. In contras t to normal megakaryocytes, which generate abundant proplatelets, cell s from these mice never produce proplatelets, even after prolonged sti mulation with c-MpI ligand. Similarly, megakaryocytes from thrombocyto penic mice with lineage-selective loss of transcription factor GATA-1 produce proplatelets very rarely. These findings establish a significa nt correlation between thrombocytopoiesis and proplatelet formation an d suggest that the latter represents a physiologic mechanism of platel et release. We further show that proplatelet formation by normal megak aryocytes and its absence in cells lacking NF-EP are independent of in teractions with adherent (stromal) cells. Similarly, thrombocytopenia in NF-E2(-/-) mice reflects intrinsic defects in the megakaryocyte lin eage. These observations improve our understanding of platelet product ion and validate the study of proplatelets in probing the underlying m echanisms. (C) 1998 by The American Society of Hematology.