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J. Biol. Chem., Vol. 281, Issue 12, 7946-7951, March 24, 2006

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The Molecular Circuitry Regulating the Switch between Iron Deficiency and Overload in Mice^*

Henry Mok¹, Agnieszka E. Mlodnicka, Matthias W. Hentze^¶, Martina Muckenthaler^||, and Armin Schumacher²

From the Department of Molecular and Human Genetics and Medical Scientist Training Program, Baylor College of Medicine, Houston, Texas 77030, ^¶European Molecular Biology Laboratory, 69117 Heidelberg, Germany,and the ^||Department of Pediatric Oncology, Hematology, and Immunology, University of Heidelberg, 69120 Heidelberg, Germany

Recent positional cloning of the radiation-induced polycythaemia (Pcm) mutation revealed a 58-bp microdeletion in the promoter region of ferroportin 1 (Fpn1), the sole cellular iron exporter identified to date. Here we report a molecular definition of the regulatory mechanisms governing the dynamic changes in iron balance in Pcm heterozygous mice between 3 and 12 weeks of age. Hepatic and/or duodenal response patterns of iron metabolism genes, such as Trfr, cybrd1, and Slc11a2, explained the transition from early postnatal iron deficiency to iron overload by 12 weeks of age. A significant delay in developmental up-regulation of hepcidin (Hamp), the pivotal hormonal regulator of iron homeostasis, correlated with high levels of Fpn1 expression in hepatic Kupffer cells and duodenal epithelial cells at 7 weeks of age. Conversely, upon up-regulation of Hamp expression at 12 weeks of age, Fpn1 expression decreased, indicative of a Hamp-mediated homeostatic loop. Hamp regulation due to iron did not appear dependent on transcription-level changes of the murine homolog of Hemojuvelin (Rgmc). Aged cohorts of Pcm mice exhibited low levels of Fpn1 expression in the context of an iron-deficient erythropoiesis and profound iron sequestration in reticuloendothelial macrophages, duodenum, and other tissues. Thus, similar to the anemia of chronic disease, these findings demonstrate decreased iron bioavailability due to sustained down-regulation of Fpn1 levels by Hamp. We conclude that regulatory alleles, such as Pcm, with highly dynamic changes in iron balance are ideally suited to interrogate the genetic circuitry regulating iron metabolism.

Received for publication, September 7, 2005 , and in revised form, December 26, 2005.

^* This work was supported in part by a National Institutes of Health research grant (to A. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables S1 and S2.

¹ Supported by an individual National Research Service Award from the NIEHS, National Institutes of Health and recipient of a National Institutes of Health training grant through the Dept. of Molecular and Human Genetics.

² To whom correspondence should be addressed: Dept. of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, S-803, Houston, TX 77030. Tel.: 713-798-6865; Fax: 713-798-8985; E-mail: armins{at}bcm.tmc.edu.

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