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1 CNRS UMR 8542, Ecole normale supérieure, 46 rue d’Ulm, 75230 Paris Cedex 05, France
2 Université Denis Diderot-Paris VII, UFR de Biologie, 2 place Jussieu, 75005 Paris, France
3 INSERM U-368, Ecole normale supérieure, 46 rue d’Ulm, 75230 Paris Cedex 05, France
4 Department of Obstetrics and Gynecology, University of Illinois at Chicago College of Medicine and Chicago Area Veterans Healthcare System (West Side Division), Chicago, IL 60612, USA
5 Laboratoire de Physiologie, Hôpital Necker, 149 rue de Sèvres, 75015 Paris, France
6 Department of Medicine, University of Illinois at Chicago College of Medicine and Chicago Area Veterans Healthcare System (West Side Division), Chicago, IL 60612, USA
7 Department of Physiology and Biophysics, University of Illinois at Chicago College of Medicine and Chicago Area Veterans Healthcare System (West Side Division), Chicago, IL 60612, USA
*Author for correspondence (e-mail: prochian{at}wotan.ens.fr)
Accepted 6 June 2002
Transgenic mice expressing the homeobox gene Hoxa5 under the control of Hoxb2 regulatory elements present a growth arrest during weeks two and three of postnatal development, resulting in proportionate dwarfism. These mice present a liver phenotype illustrated by a 12-fold increase in liver insulin-like growth factor binding protein 1 (IGFBP1) mRNA and a 50% decrease in liver insulin-like growth factor 1 (IGF1) mRNA correlated with a 50% decrease in circulating IGF1. We show that the Hoxa5 transgene is expressed in the liver of these mice, leading to an overexpression of total (endogenous plus transgene) Hoxa5 mRNA in this tissue. We have used several cell lines to investigate a possible physiological interaction of Hoxa5 with the main regulator of IGFBP1 promoter activity, the Forkhead box transcription factor FKHR. In HepG2 cells, Hoxa5 has little effect by itself but inhibits the FKHR-dependent activation of the IGFBP1 promoter. In HuF cells, Hoxa5 cooperates with FKHR to dramatically enhance IGFBP1 promoter activity. This context-dependent physiological interaction probably corresponds to the existence of a direct interaction between Hoxa5 and FKHR and FoxA2/HNF3ß, as demonstrated by pull-down experiments achieved either in vitro or after cellular co-expression. In conclusion, we propose that the impaired growth observed in this transgenic line relates to a liver phenotype best explained by a direct interaction between Hoxa5 and liver-specific Forkhead box transcription factors, in particular FKHR but also Foxa2/HNF3ß. Because Hoxa5 and homeogenes of the same paralog group are normally expressed in the liver, the present results raise the possibility that homeoproteins, in addition to their established role during early development, regulate systemic physiological functions.
Key words: Hoxa5, Liver, Postnatal growth, Winged-helix/Forkhead box, Foxa2, HNF3ß, FKHR, IGFBP1, IGF1, Mouse
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