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Reprinted with permission from the National Academy
of Sciences, USA;
Copyright 2001 National Academy of Sciences, U.S.A. Proceedings
of the National Academy of Sciences, USA; Vol 98; Issue 12; 6842-6847;
June 5, 2001
Essential role for Mammalian Copper Transporter Ctr1 in Copper Homeostasis
and Embryonic Development
Story by Jaekwon Lee*, Joseph R. Prohaska†, and Dennis J. Thiele*‡
The trace metal copper (Cu) plays an essential role in biology as
a cofactor for many enzymes that include Cu, Zn superoxide dismutase,
cytochrome oxidase, ceruloplasmin, lysyl oxidase, and dopamine ß-hydroxylase.
Consequently, Cu transport at the cell surface and the delivery of
Cu to intracellular compartments are critical events for a wide variety
of biological processes. The components that orchestrate intracellular
Cu trafficking and their roles in Cu homeostasis have been elucidated
by the studies of model microorganisms and by the characterizations
of molecular basis of Cu-related genetic diseases, including Menkes
disease and Wilson disease. However, little is known about the mechanisms
for Cu uptake at the plasma membrane and the consequences of defects
in this process in mammals. Here, we show that the mouse Ctr1
gene encodes a component of the Cu transport machinery and that mice
heterozygous for Ctr1 exhibit tissue-specific defects in copper
accumulation and in the activities of copper-dependent enzymes. Mice
completely deficient for Ctr1 exhibit profound growth and developmental
defects and die in utero in mid-gestation. These results demonstrate
a crucial role for Cu acquisition through the Ctr1 transporter for
mammalian Cu homeostasis and embryonic development.
##
Department of Biological Chemistry, University of Michigan Medical
School, Ann Arbor, MI 48109-0606; and †Department of Biochemistry
and Molecular Biology, University of Minnesota, Duluth, MN 55812
‡To whom reprint requests should be addressed.
E-mail: dthiele@umich.edu
Edited by William S. Sly, Saint Louis University School of Medicine,
St. Louis, MO, and approved April 3, 2001 (received for review
February 5, 2001)
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