Hepatocyte Nuclear Factor 3β (Foxa2) Is Dispensable for Maintaining the Differentiated State of the Adult Hepatocyte

Abstract

Liver-specific gene expression is controlled by a heterogeneous group of hepatocyte-enriched transcription factors. One of these, the winged helix transcription factor hepatocyte nuclear factor 3β (HNF3β or Foxa2) is essential for multiple stages of embryonic development. Recently, HNF3β has been shown to be an important regulator of other hepatocyte-enriched transcription factors as well as the expression of liver-specific structural genes. We have addressed the role of HNF3β in maintenance of the hepatocyte phenotype by inactivation of HNF3β in the liver. Remarkably, adult mice lackingHNF3β expression specifically in hepatocytes are viable, with histologically normal livers and normal liver function. Moreover, analysis of >8,000 mRNAs by array hybridization revealed that lack of HNF3β affects the expression of only very few genes. Based on earlier work it appears that HNF3β plays a critical role in early liver development; however, our studies demonstrate that HNF3β is not required for maintenance of the adult hepatocyte or for normal liver function. This is the first example of such functional dichotomy for a tissue specification transcription factor.

ACKNOWLEDGMENTS

N.J.S. and S.-L.A. contributed equally to this work.

We are grateful to M. Birnbaum, L. Greenbaum, and M. A. Lazar for critical reading of the manuscript; T. Jessell for providing the HNF3β antibody; K. Zaret, P. Bossard, and L. Greenbaum for providing assistance with the preparation of nuclear extracts and the EMSA; R. Ahima for assistance with the glucose tolerance test; and G. Schütz for his support during the initial phase of the project.

Our studies were facilitated by the Center for Molecular Studies in Digestive and Liver Disease at the University of Pennsylvania (P30 DK50306). This work was supported by the NIDDK (RO1 DK55342 to KHK and RO1s DK42502 and DK42612 to MAM), the Association pour la Recherche sur le Cancer, the Institut National de la Santé et de la Recherche Médicale, the Centre National de la Recherche Scientifique, and the Centre Hospitalier Universitaire Régional (grant to S.L.A.). N.J.S. was supported through an NIH pre-doctoral training grant (5-T32-GM08216).