Specific contribution of the erythropoietin gene 3' enhancer to hepatic erythropoiesis after late embryonic stages

Norio Suzuki, Naoshi Obara, Xiaoqing Pan, Miho Watanabe, Kou Ichi Jishage, Naoko Minegishi, Masayuki Yamamoto

Research output: Contribution to journalArticlepeer-review

40 Citations (Scopus)

Abstract

Erythropoietin (Epo) is secreted from the liver and kidney, where Epo production is strictly regulated at the transcriptional level in a hypoxia- and/or anemia-inducible manner. Here, we examined the in vivo function of the enhancer located 3' to the Epo gene (EpoE-3'). Reporter transgenic-mouse analyses revealed that the EpoE-3' enhancer is necessary and sufficient for the liver-specific and hypoxia-responsive expression of the gene after embryonic day 14.5 (E14.5). However, the enhancer is dispensable for Epo gene expression in the kidney and early-stage embryonic liver. Genetic removal of EpoE-3' from the endogenous Epo gene resulted in mice with severe anemia at late embryonic and neonatal stages due to defects in hepatic erythropoiesis, but early hepatic and splenic erythropoiesis was not affected. The mutant mice recover from the anemia in the juvenile period when major Epo production switches from the liver to the kidney. These results demonstrate that EpoE-3' is necessary for late hepatic erythropoiesis by specifically supporting paracrine production of Epo in the liver. In contrast, Epo production in the kidney utilizes distinct regulatory machinery and supports erythropoiesis in the bone marrow and spleen in adult animals.

Original languageEnglish
Pages (from-to)3896-3905
Number of pages10
JournalMolecular and cellular biology
Volume31
Issue number18
DOIs
Publication statusPublished - 2011 Sep

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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