The initiation of liver development is dependent on Foxa transcription factors

Foxa1 and Foxa2 regulatory proteins have been identified as essential for the specification of the cells that form the liver in the vertebrate embryo. Mouse embryos lacking these proteins are essentially liver-less, with no liver bud in the foregut endoderm. The Foxa genetic system may prove to be a useful model for the study of the molecular control of organogenesis in general, since as well as the liver, this part of the embryo forms the lungs, thyroid and pancreas. 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.