Thrombopoietin rescues in vitro erythroid colony formation from mouse embryos lacking the erythropoietin receptor

Mark W. Kieran, Andrew C. Perkins, Stuart H. Orkin, Leonard I. Zon

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Abstract

The interaction of the hormone erythropoietin and its receptor (EpoR) is thought to be required for normal hematopoiesis. To define the role of EpoR in this process, the murine EpoR was disrupted by homologous recombination. Mice lacking the EpoR died in utero at embryonic day 11-12.5 with severe anemia. Embryonic erythropoiesis was markedly diminished, while fetal liver hematopoiesis was blocked at the proerythroblast stage. Other cell types known to express EpoR, including megakaryocytes, mast, and neural cells were morphologically normal. Reverse transcription-coupled PCR analysis of RNA from embryonic yolk sac, peripheral blood, and fetal liver demonstrated near normal transcripts levels for EKLF, thrombopoietin (Tpo), c-MPL, GATA-1, GATA-2, and α- and embryonic βH1-globin but none for adult βmaj-globin. While colony-forming unit-erythroid (CFU-E) and burst-forming unit-erythroid (BFU-E) colonies were not present in cultures derived from EpoR-/- liver or yolk sac cells, hemoglobin-containing BFU-E colonies were detected in cultures treated with recombinant Tpo and Kit ligand or with Tpo and interleukin 3 and 11. Rescued BFU-E colonies expressed adult β-globin and c- MPL and appeared morphologically normal. Thus, erythroid progenitors are formed in vivo in mice lacking the EpoR, and our studies demonstrate thai a signal transmitted through the Tpo receptor c-MPL stimulates proliferation and terminal differentiation of these progenitors in vitro.

Original languageEnglish
Pages (from-to)9126-9131
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume93
Issue number17
DOIs
Publication statusPublished - 20 Aug 1996
Externally publishedYes

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