International Mammalian Genome Society

The 16th International Mouse Genome Conference (2002)


POSTER 123 - TARGETED EXPRESSION OF THE HEMOCHROMATOSIS GENE (HFE1) ALONG THE INTESTINAL CRYPT-VILLUS AXIS PROVIDES EVIDENCE THAT HFE REGULATES A FUNCTIONAL CROSS-TALK BETWEEN CRYPT AND VILLI ENTEROCYTES

P Fergelot
CNRS UMR6061

1) Abgueguen E 1) Ropert-Bouchet M, 1) Orhant M, 2) Grimber G, 3) Jouan H, 4) Gilfillan S, 5) Bahram S, 1) J-Y Le Gall
1) CNRS UMR6061  2) INSERM-CreS,Centre de Recherche d’Immunologie et d’Hématologie, Strasbourg  3) INSERM U567, CNRS UMR8104, laboratoire membre de l’IFR116.  4) Faculté de Médecine de Rennes  5) Washington University School of Medicine, St. Louis

Hereditary hemochromatosis (HH), a common autosomal recessive disorder due to a mutation in HFE1, is characterized by excessive absorption of dietary iron. Little is known however of the apparently complex pathophysiology of HFE involvement in the process of non-heme iron uptake and transport to the blood. Here in order to tackle the issue in vivo we decided to target HFE expression exclusively to the relevant tissue, intestinal epithelium. This was achieved by putting HFE under transcriptional control of the rat fatty acid binding protein (Fabpi) promoter. Quite unexpectedly, two out of three Fabpi-HFE transgenic lines had significantly elevated serum transferrin saturation levels in comparison to those of normal littermates. By a careful, layer by layer analysis of transgene expression along the crypt-villus axis, we showed that the ectopic expression of transgenic HFE in the differentiated villi enterocytes was responsible for ferric hyper-absorption, a phenomenon exacerbated in the absence of endogenous HFE expression, which we assessed by crossing the transgene onto an HFE-/- (knockout) background. The third line expressing the transgene in the crypts but not in differentiated enterocytes had lower serum transferrin saturation and ferritin levels. Moerover these mice displayed iron deposition and elevated ferritin expression in the duodenum epithelium throughout the crypt-villus axis. This forced dichotomy between the absence of HFE in the crypt, expression in the villi and overexpression of HFE in the crypt provides experimental support that HFE regulates the cross-talk between the crypt and villi enterocytes, thereby modulating the avidity of duodenal epithelium for dietary iron.


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