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The initiation of liver development is dependent on Foxa transcription factors

Nature volume 435, pages 944–947 (2005)Cite this article

Abstract

The specification of the vertebrate liver is thought to occur in a two-step process, beginning with the establishment of competence within the foregut endoderm for responding to organ-specific signals, followed by the induction of liver-specific genes. On the basis of expression and in vitro studies, it has been proposed that the Foxa transcription factors establish competence by opening compacted chromatin structures within liver-specific target genes1. Here we show that Foxa1 and Foxa2 (forkhead box proteins A1 and A2) are required in concert for hepatic specification in mouse. In embryos deficient for both genes in the foregut endoderm, no liver bud is evident and expression of the hepatoblast marker alpha-fetoprotein (Afp) is lost. Furthermore, Foxa1/Foxa2-deficient endoderm cultured in the presence of exogenous fibroblast growth factor 2 (FGF2) fails to initiate expression of the liver markers albumin and transthyretin. Thus, Foxa1 and Foxa2 are required for the establishment of competence within the foregut endoderm and the onset of hepatogenesis.

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Figure 1: The Foxa1-/-;Foxa2LoxP/LoxP;Foxa3-Cre mutant embryo.
Figure 2: Foxa1-/-;Foxa2LoxP/LoxP;Foxa3-Cre embryos fail to initiate the hepatic programme.
Figure 3: In vitro activation of the hepatic programme by FGF is abrogated in Foxa1-/-;Foxa2LoxP/LoxP;Foxa3-Cre embryos.

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Acknowledgements

We thank A. Calmont for technical help with explant culture. We are also grateful for technical support from the Morphology Core at the University of Pennsylvania. This work was supported by an award from the National Institutes of Health (NIH) to K.H.K., a Children's Digestive Health and Nutrition Foundation Young Investigator Award to J.R.F. and by training grants from the NIH to C.S.L. and J.R.F.

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  1. Catherine S. Lee and Joshua R. Friedman: *These authors contributed equally to this work

Authors and Affiliations

  1. Department of Genetics,

    Catherine S. Lee, Joshua R. Friedman, James T. Fulmer & Klaus H. Kaestner

  2. Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, 19104, USA

    Joshua R. Friedman

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  1. Catherine S. Lee
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  2. Joshua R. Friedman
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  4. Klaus H. Kaestner
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Correspondence to Klaus H. Kaestner.

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Lee, C., Friedman, J., Fulmer, J. et al. The initiation of liver development is dependent on Foxa transcription factors. Nature 435, 944–947 (2005). https://doi.org/10.1038/nature03649

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