| |
|
 |
Copper is crucial for embryonic development,
say U-M scientists
Embargoed for release at 5 p.m. on June 4, 2001
Without copper transport gene, mice—and probably people—die
before birth
ANN ARBOR, Mich. -- Copper could be more important to the health of
your unborn baby than folic acid, giving up smoking or abstaining
from alcohol—according to a new study by scientists at the University
of Michigan Medical School.
In the June 5 issue of the Proceedings of the National Academy
of Sciences, U-M scientists report that copper and a protein called
Ctr1, which helps copper get inside cells, is essential for normal
embryonic development in mice. Although scientists knew that Ctr1
was involved in copper transport in yeast microorganisms, no one knew
exactly how the gene worked in mammals until now.
Since the genetic structure and function of Ctr1 is nearly identical
in mice and humans, it is very likely that Ctr1 is essential for human
embryonic development, as well," says Dennis J. Thiele, Ph.D., a professor
of biological chemistry in the U-M Medical School, who directed the
PNAS study.
In recent studies with fruit flies, mice and human cells, Thiele found
Ctr1 copper transport proteins and gene sequences in every species.
"Ctr1 appears to have been conserved throughout evolutionary development,
because it is so effective at bringing copper across membranes and
into cells," he says.
"Ctr1 escorts copper through the cells surface membrane and
then hands it off to at least three other proteins, which deliver
it to specific compartments inside the cell," Thiele says. "Its like
a copper relay, and Ctr1 is the main gate."
A related paper by scientists from Washington University at St. Louis,
published in the same issue of PNAS, describes the role of ATOX1,
one of three other proteins in this intracellular copper relay.
"Copper is an essential micronutrient, which is required for
vital biochemical reactions within cells," Thiele says. "Without copper,
cells cant produce energy, metabolize iron or detoxify free radicals.
Without copper, we cant grow blood vessels, synthesize neuropeptides
that control muscle contractions, or make the collagen that gives
our skin its elasticity."
Thiele studied yeast microorganisms for 17 years to learn how cells
process copper. "Our work with yeast, and research by other scientists,
was the key to finding the transporter proteins," he says.
In the PNAS study, Thieles research team found that expression of
the Ctr1 gene in human kidney cells stimulated a 30-fold increase
in copper uptake by the cells. U-M scientists then used genetic engineering
technology to create knock-out mice that were missing one of two alleles—or
copies of the Ctr1 gene—found in normal mice.
Although these heterozygous mice appeared and acted normal, U-M researchers
found that their brains and spleens contained about half as much copper
as was found in normal littermates. Since the ability to metabolize
iron—another critical nutrient—depends on copper, it was
not a surprise to find that iron levels were lower in organs from
heterozygous mice than from normal littermates.
The big surprise came when U-M researchers bred male and female heterozygous
mice to see what would happen to mice without either copy of the Ctr1
gene. Of 378 mouse pups born, however, not one was found to be missing
both copies of the gene. When Thiele examined mouse embryos from these
crosses, he discovered that embryos without the Ctr1 gene all died
10 to 12 days after fertilization. In addition, all these embryos
were much smaller than normal and had major abnormalities in organ
and cell development.
" I anticipated the importance of copper in development, but
I didnt expect it to be so critical that all the mouse embryos without
Ctr1 would die before birth," Thiele said. "Based on these results,
it wouldnt surprise me to find that human embryos lacking both copies
of Ctr1 are aborted spontaneously during pregnancy."
T o test whether copper supplements would help, U-M researchers added
it to the drinking water of female experimental mice three weeks before
and during their pregnancies. Although they received 50 to 100 times
more copper than control mice, the effect on their embryos was unchanged.
"These data suggest there is no alternate system for copper uptake
into cells that can compensate for loss of the plasma membrane Ctr1
transporter, and that the presence of at least one functional copy
of the Ctr1 copper transporter gene is essential for normal embryonic
development," Thiele says. "In addition, reduced copper accumulation
in both brain and spleen from Ctr1 heterozygous mice indicates that
two functional copies of Ctr1 are critical for maintaining normal
copper balance."
Copper deprivation is particularly dangerous for children and infants,
according to Thiele. Children born with a genetic condition called
Menkes disease suffer irreversible damage, because copper remains
trapped in their intestinal cells, where it is unavailable to the
many copper-requiring enzymes in the body. Patients with Wilson disease
develop cirrhosis and nerve degeneration due to their inability to
distribute copper properly.
The U-M is offering non-exclusive licenses for use of Ctr1 knock-out
mice as a commercial research tool and will provide mice without charge
to academic researchers.
This research was supported by grants from the National Institutes
of Health, the International Copper Association and the American Heart
Association. Jaekwon Lee, Ph.D., U-M post-doctoral research fellow,
and Joseph R. Prohaska, Ph.D., professor of biochemistry and molecular
biology at the University of Minnesota-Duluth, were co-authors of
the study.
CONTACT:
Sally Pobojewski 734-764-2220,
or via email at pobo@umich.edu
|
|
|  |
|
