Specific Contribution of the Erythropoietin Gene 3′ Enhancer to Hepatic Erythropoiesis after Late Embryonic Stages
- 1 September 2011
- journal article
- Published by Taylor & Francis Ltd in Molecular and Cellular Biology
- Vol. 31 (18), 3896-3905
- https://doi.org/10.1128/mcb.05463-11
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.Keywords
This publication has 53 references indexed in Scilit:
- Hepatic HIF-2 regulates erythropoietic responses to hypoxia in renal anemiaBlood, 2010
- Generating specificity and diversity in the transcriptional response to hypoxiaNature Reviews Genetics, 2009
- Regulation of adult erythropoiesis by prolyl hydroxylase domain proteinsBlood, 2008
- Wt1 and retinoic acid signaling are essential for stellate cell development and liver morphogenesisDevelopmental Biology, 2007
- Hypoxia-inducible factor–2 (HIF-2) regulates hepatic erythropoietin in vivoJCI Insight, 2007
- Embryonic development of the liverHepatology, 2005
- Role of CBP in regulating HIF-1-mediated activation of transcriptionJournal of Cell Science, 2005
- Roles of Brahma and Brahma/SWI2-Related Gene 1 in Hypoxic Induction of the Erythropoietin GeneOnline Journal of Public Health Informatics, 2004
- Differentiating the functional role of hypoxia‐inducible factor (HIF)‐1α and HIF‐2α (EPAS‐1) by the use of RNA interference: erythropoietin is a HIF‐2α target gene in Hep3B and Kelly cellsThe FASEB Journal, 2004
- Hepatocyte nuclear factor 4α controls the development of a hepatic epithelium and liver morphogenesisNature Genetics, 2003