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Blood, Vol. 93 No. 12 (June 15), 1999:
pp. 4406-4417
Cellular and Subcellular Localization of the Nramp2 Iron
Transporter in the Intestinal Brush Border and Regulation by
Dietary Iron
F. Canonne-Hergaux,
S. Gruenheid,
P. Ponka, and
P. Gros
From the Departments of Biochemistry and Physiology, McGill
University, Montreal, Quebec, Canada; and the Lady Davis Institute for
Medical Research, Jewish General Hospital, Montreal, Quebec, Canada.
Genetic studies in animal models of microcytic anemia and
biochemical studies of transport have implicated the Nramp2
gene in iron transport. Nramp2 generates two alternatively
spliced mRNAs that differ at their 3' untranslated region by the
presence or absence of an iron-response element (IRE) and that encode
two proteins with distinct carboxy termini. Antisera raised against Nramp2 fusion proteins containing either the carboxy or amino termini
of Nramp2 and that can help distinguish between the two Nramp2 protein
isoforms (IRE: isoform I; non-IRE: isoform II) were generated. These
antibodies were used to identify the cellular and subcellular
localization of Nramp2 in normal tissues and to study possible
regulation by dietary iron deprivation. Immunoblotting experiments with
membrane fractions from intact organs show that Nramp2 is expressed at
low levels throughout the small intestine and to a higher extent in
kidney. Dietary iron starvation results in a dramatic upregulation of
the Nramp2 isoform I in the proximal portion of the duodenum only,
whereas expression in the rest of the small intestine and in kidney
remains largely unchanged in response to the lack of dietary iron. In
proximal duodenum, immunostaining studies of tissue sections show that
Nramp2 protein expression is abundant under iron deplete condition and
limited to the villi and is absent in the crypts. In the villi,
staining is limited to the columnar absorptive epithelium of the mucosa
(enterocytes), with no expression in mucus-secreting goblet cells or in
the lamina propria. Nramp2 expression is strongest in the apical two
thirds of the villi and is very intense at the brush border of the
apical pole of the enterocytes, whereas the basolateral membrane of
these cells is negative for Nramp2. These results strongly suggest that Nramp2 is indeed responsible for transferrin-independent iron uptake in
the duodenum. These findings are discussed in the context of overall
mechanisms of iron acquisition by the body.
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