Nature Genetics
21, 396 - 399 (1999)
doi:10.1038/7727
Transferrin receptor is necessary for development of erythrocytes and
the nervous systemJoanne E. Levy1, 3, 5, Ou Jin1, 2, Yuko Fujiwara1, 2, Frank Kuo4
& Nancy Andrews1, 2, 61
Division of Hematology/Oncology, Children's Hospital,
Howard Hughes Medical Institute
2
Howard Hughes Medical Institute
3
Division of Hematology, Brigham and Women's Hospital
4
Department of Pathology, Brigham and Women's Hospital
5
Department of Medicine, Harvard Medical School,
Boston, Massachusetts 02115, USA. 6
Department of Pediatrics, Harvard Medical School,
Boston, Massachusetts 02115, USA.
Correspondence should be addressed to Nancy Andrews nandrews@rascal.med.harvard.eduPlasma iron circulates bound to transferrin (Trf), which solubilizes the
ferric ion and attenuates its reactivity. Diferric Trf interacts with cell-surface
Trf receptor (Trfr) to undergo receptor-mediated endocytosis into specialized
endosomes. Endosomal acidification leads to iron release, and iron is transported
out of the endosome through the activity of divalent metal transporter 1 (DMT1,
formerly Nramp2), a transmembrane iron transporter that functions only at
low pH (ref. 1). Trf and Trfr then return to the
cell surface for reuse, completing a highly efficient cycle. Although the
Trf cycle is assumed to be the general mechanism for cellular iron uptake,
this has not been validated experimentally. Mice with hypotransferrinaemia
(hpx) have little or no plasma Trf (Refs 2,3). They have severe anaemia, indicating that the Trf cycle
is essential for iron uptake by erythroid cells3. Other
hpx tissues, however, are generally normal, and there is a paradoxical
increase in intestinal iron absorption and iron storage3,
4.
To test the hypothesis that the Trf cycle has unique importance for erythropoiesis,
we disrupted the Trfr gene in mice. This results in elimination of
the Trf cycle, but leaves other Trf functions intact. Mice lacking Trfr have
a more severe phenotype than hpx mice, affecting both erythropoiesis
and neurologic development. Furthermore, haploinsufficiency for Trfr results
in impaired erythroid development and abnormal iron homeostasis.
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