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A developmental transition in definitive erythropoiesis: erythropoietin expression is sequentially regulated by retinoic acid receptors and HNF4

Makita, Takako and Hernandez-Hoyos, Gabriela and Chen, Tim Hung-Po and Wu, Hong and Rothenberg, Ellen V. and Sucov, Henry M. (2001) A developmental transition in definitive erythropoiesis: erythropoietin expression is sequentially regulated by retinoic acid receptors and HNF4. Genes and Development, 15 (7). pp. 889-901. ISSN 0890-9369. PMCID PMC312661. doi:10.1101/gad.871601.

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The cytokine erythropoietin (Epo) promotes erythropoietic progenitor cell proliferation and is required for erythropoietic differentiation. We have found that the Epo gene is a direct transcriptional target gene of retinoic acid signaling during early erythropoiesis (prior to embryonic day E12.5) in the fetal liver. Mouse embryos lacking the retinoic acid receptor gene RXRα have a morphological and histological phenotype that is comparable with embryos in which the Epo gene itself has been mutated, and flow cytometric analysis indicates that RXRα-deficient embryos are deficient in erythroid differentiation. Epo mRNA levels are reduced substantially in the fetal livers of RXRα ^(−/−)embryos at E10.25 and E11.25, and genetic analysis shows that theRXRα and Epo genes are coupled in the same pathway. We furthermore show that the Epo gene is retinoic acid inducible in embryos, and that the Epo gene enhancer contains a DR2 sequence that represents a retinoic acid receptor-binding site and a retinoic acid receptor transcriptional response element. However, unlike Epo-deficient embryos that die from anemia, the erythropoietic deficiency in RXRα ^(−/−) embryos is transient; Epo mRNA is expressed at normal levels by E12.5, and erythropoiesis and liver morphology are normal by E14.5. We show that HNF4, like RXRα a member of the nuclear receptor family, is abundantly expressed in fetal liver hepatocytes, and is competitive with retinoic acid receptors for occupancy of the Epo gene enhancer DR2 element. We propose that Epo expression is regulated during the E9.5–E11.5 phase of fetal liver erythropoiesis by RXRα and retinoic acid, and that expression then becomes dominated by HNF_4 activity from E11.5 onward. This transition may be responsible for switching regulation of Epo expression from retinoic acid control to hypoxic control, as is found throughout the remainder of life.

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Rothenberg, Ellen V.0000-0002-3901-347X
Additional Information:© 2001 Cold Spring Harbor Laboratory Press. The Authors acknowledge that six months after the full-issue publication date, the Article will be distributed under a Creative Commons CC-BY-NC License (Attribution-NonCommercial 4.0 International License, Received December 6, 2000; revised version accepted February 7, 2001. We thank Todd Leff for provision of CMV-dnHNF4, Ron Evans for provision of CMX–hRXRα and CMX–hRARα, and Francie Sladek for provision of pSG5–rHNF4α1. This work was supported in its early phase by a pilot/feasibility project grant (to H.M.S.) as a component of the University of Southern California Research Center for Liver Diseases (PHS grant no. DK48522). G.H.-H. was supported by the Stowers Institute for Medical Research. H.W. is an Assistant Investigator of the Howard Hughes Medical Institute. T.C. was supported by a predoctoral fellowship from the American Heart Association. The publication costs of this article were defrayed in part by payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 USC section 1734 solely to indicate this fact.
Funding AgencyGrant Number
Stowers Institute for Medical ResearchUNSPECIFIED
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
American Heart AssociationUNSPECIFIED
Subject Keywords:Erythropoiesis; HNF4; retinoic acid regulation; RXRα; fetal liver; DR2
Issue or Number:7
PubMed Central ID:PMC312661
Record Number:CaltechAUTHORS:20170216-142557366
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Official Citation:Makita T, Hernandez-Hoyos G, Chen TH-P, Wu H, Rothenberg EV, Sucov HM. A developmental transition in definitive erythropoiesis: erythropoietin expression is sequentially regulated by retinoic acid receptors and HNF4. Genes & Development. 2001;15(7):889-901. doi:10.1101/gad.871601.
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:74388
Deposited By: George Porter
Deposited On:16 Feb 2017 22:45
Last Modified:11 Nov 2021 05:26

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