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Blood, Vol. 94 No. 9 (November 1), 1999:
pp. 3037-3047
Pathophysiology of Thrombocytopenia and Anemia in Mice Lacking
Transcription Factor NF-E2
Jack Levin,
Jin-Peng Peng,
Georgiann R. Baker,
Jean-Luc Villeval,
Patrick Lecine,
Samuel A. Burstein, and
Ramesh A. Shivdasani
From the Department of Laboratory Medicine, University of California
School of Medicine and Veterans Administration Medical Center, San
Francisco, CA; W.K. Warren Medical Research Institute at The University
of Oklahoma Health Sciences Center, Oklahoma City, OK; and the
Departments of Adult Oncology and Medicine, Dana-Farber Cancer
Institute, Brigham & Women's Hospital, and Harvard Medical School,
Boston, MA.
Expression of the p45 subunit of transcription factor NF-E2 is
restricted to selected blood cell lineages, including megakaryocytes and developing erythrocytes. Mice lacking p45 NF-E2 show profound thrombocytopenia, resulting from a late arrest in megakaryocyte differentiation, and a number of red blood cell defects, including anisocytosis and hypochromia. Here we report results of studies aimed
to explore the pathophysiology of these abnormalities. Mice lacking
NF-E2 produce very few platelet-like particles that display highly
disorganized ultrastructure and respond poorly to platelet agonists,
features consistent with the usually lethal hemorrhage in these
animals. Thrombocytopenia was evident during fetal life and was not
corrected by splenectomy in adults. Surprisingly, fetal
NF-E2-deficient megakaryocyte progenitors showed reduced proliferation
potential in vitro. Thus, NF-E2 is required for regulated megakaryocyte
growth as well as for differentiation into platelets. All the erythroid
abnormalities were reproduced in lethally irradiated wild-type
recipients of hematopoietic cells derived from NF-E2-null fetuses.
Whole blood from mice lacking p45 NF-E2 showed numerous small red blood
cell fragments; however, survival of intact erythrocytes in vivo was
indistinguishable from control mice. Considered together, these
observations indicate a requirement for NF-E2 in generating normal
erythrocytes. Despite impressive splenomegaly at baseline, mice lacking
p45 NF-E2 survived splenectomy, which resulted in increased
reticulocyte numbers. This reveals considerable erythroid reserve
within extra-splenic sites of hematopoiesis and suggests a role for the
spleen in clearing abnormal erythrocytes. Our findings address distinct
aspects of the requirements for NF-E2 in blood cell homeostasis and
establish its roles in proper differentiation of megakaryocytes and erythrocytes.
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