Invited Symposium: Iron Transport



Positional Cloning of DMT1

DMT1 is a divalent metal transporter

Targeted Disruption of the TfR Gene



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Iron Transport: Lessons from Anemic Mice

Andrews, N.C. (Howard Hughes Medical Institute, Children's Hospital, Harvard Medical School, USA)
Fleming, M.D. (Children's Hospital, Brigham and Women's Hospital, Harvard Medical School, USA)
Levy, (Children's Hospital, Brigham and Women's Hospital, Harvard Medical School, USA)

Contact Person: Nancy C. Andrews (andrews_n@a1.tch.harvard.edu)


Our laboratory has used animal models with defects in various aspects of iron transport and utilization to study these processes. We have taken two approaches -- positional cloning of disease genes from rodents with inherited iron deficiency anemias, and targeted disruption of iron-related genes to produce new mouse models. We will discuss examples of each approach. (1) Positional cloning of a transmembrane iron transporter. Until recently, it was not known how iron moves across biological membranes in mammals. To investigate this problem, we undertook genetic mapping and positional cloning of the genes defective in microcytic anemia (mk) mice and belgrade (b) rats. Both of these strains have defective intestinal iron transport, and defective erythroid iron utilization. We mapped the mk mutation to the telomeric portion of mouse chromosome 15, and the b mutation to the centromeric portion of rat chromosome 7. In both cases, the mutations lay within the gene encoding a 12 transmembrane domain protein, formerly referred to as Nramp2. The mk and b mutations are identical, resulting in an arginine for glycine substitution at amino acid 185 of the protein. Functional experiments indicated that this protein, now designated divalent metal transporter 1 (DMT1), stimulates iron uptake in transfected cells. Gunshin, Hediger and co-workers showed that DMT1 functions as a proton-coupled transporter in a Xenopus oocyte expression assay. DMT1 can be found on the cell surface, and in association with transferrin cycle endosomes. We conclude that it is an important transmembrane iron transporter in intestinal cells and in erythroid precursors. (2) Targeted disruption of the transferrin receptor gene. Iron uptake by erythroid cells is highly dependent upon the function of the transferrin cycle. We have disrupted the gene encoding the transferrin receptor (TfR) in mouse embryonic stem cells, and used these cells to transmit the mutant allele through the mouse germline. We have found that TfR -/- mice die during midgestation, in part from anemia, and in part from specific neural defects. TfR +/- mice develop normal, but exhibit persistent abnormalities in erythropoiesis. We conclude that TfR plays a critical role in erythropoiesis, and a previously undocumented role in maintenance of developing neurologic structures.

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Presentation Number SAandrews0487
Keywords: iron, erythroid, transport, anemia, mouse

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Andrews, N.C.; Fleming, M.D.; Levy, ; (1998). Iron Transport: Lessons from Anemic Mice. Presented at INABIS '98 - 5th Internet World Congress on Biomedical Sciences at McMaster University, Canada, Dec 7-16th. Invited Symposium. Available at URL http://www.mcmaster.ca/inabis98/templeton/andrews0487/index.html
© 1998 Author(s) Hold Copyright