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Blood, Vol. 92 No. 5 (September 1), 1998:
pp. 1608-1616
Mice Lacking Transcription Factor NF-E2 Provide In Vivo
Validation of the Proplatelet Model of Thrombocytopoiesis and Show
a Platelet Production Defect That Is Intrinsic to Megakaryocytes
Patrick Lecine,
Jean-Luc Villeval,
Paresh Vyas,
Bethany Swencki,
Yuhui Xu, and
Ramesh A. Shivdasani
From the Department of Adult Oncology, Dana-Farber Cancer Institute,
Boston, MA; the Department of Medicine, Children's Hospital Medical
Center, Boston, MA; and the Department of Medicine, Harvard Medical
School, Boston, MA.
Mechanisms of platelet production and release by mammalian
megakaryocytes are poorly understood. We used thrombocytopenic knockout
mice to better understand these processes. Proplatelets are filamentous
extensions of terminally differentiated megakaryocytes that are thought
to represent one mechanism of platelet release; however, these
structures have largely been recognized in cultured cells and there has
been no correlation between thrombocytopoiesis in vivo and proplatelet
formation. Mice lacking transcription factor NF-E2 have a late arrest
in megakaryocyte maturation, resulting in profound thrombocytopenia. In
contrast to normal megakaryocytes, which generate abundant
proplatelets, cells from these mice never produce proplatelets, even
after prolonged stimulation with c-Mpl ligand. Similarly,
megakaryocytes from thrombocytopenic mice with lineage-selective loss
of transcription factor GATA-1 produce proplatelets very rarely. These
findings establish a significant correlation between thrombocytopoiesis
and proplatelet formation and suggest that the latter represents a
physiologic mechanism of platelet release. We further show that
proplatelet formation by normal megakaryocytes and its absence in cells
lacking NF-E2 are independent of interactions with adherent (stromal)
cells. Similarly, thrombocytopenia in NF-E2 / mice
reflects intrinsic defects in the megakaryocyte lineage. These
observations improve our understanding of platelet production and
validate the study of proplatelets in probing the underlying mechanisms.
© 1998 by The American Society of Hematology.
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