Researchers identify cells that cause nervous system disease
Microscope image of mouse Schwann cells, shown in red with the cell
nuclei stained blue. Photo credit: Nancy Joseph, University of
Michigan.
Two teams of University of Michigan researchers have tracked down the
cells responsible for neurofibromatosis type1, a disfiguring,
incurable condition and one of the most common hereditary disorders.
"We now know what cells to target. And that's a big step toward new
therapies," said Sean Morrison, director of the U-M Center for Stem
Cell Biology and leader of one of the research teams. The other group
was headed by Yuan Zhu of the U-M Medical School.
Neurofibromatosis type 1, or NF1, is a peripheral nervous system
condition that afflicts one in 3,500 Americans. Symptoms normally
begin to appear by age 10. Though most cases are mild, the disease
can lead to disfigurement, learning disabilities, blindness, skeletal
abnormalities, loss of limbs and, occasionally, lethal malignancies.
NF1 causes benign tumors to grow around peripheral nerves; in 3 to 5
percent of the cases, the tumors later become malignant. The most
common NF1 tumors are called neurofibromas.
Researchers have long wondered which of the body's cell types
triggers the formation of neurofibromas: Is it the Schwann cells,
which form the protective myelin sheath around nerve fibers, or is
the true culprit the stem cells that give rise to Schwann cells
during fetal development? The answer has implications for the
development of drug therapies.
The two U-M studies demonstrate that a special type of Schwann cell
is likely to blame, not stem cells. Both reports will be published
Feb. 5 in the journal Cancer Cell.
"People have increasingly focused on the link between stem cells and
cancer," said Morrison, a U-M Life Sciences Institute researcher and
a Howard Hughes Medical Institute investigator. "What we're saying
here is that it's not always the stem cells. The mature cells, even
in the nervous system, can give rise to these cancers."
In 1990 two teams—one led by former U-M geneticist Francis Collins—
discovered that NF1 is caused by one enormous gene on chromosome 17.
NF1 is the most common neurological disorder caused by a single gene.
The NF1 gene makes a large and complex protein called neurofibromin,
which acts as a molecular brake to prevent nervous system cells from
overmultiplying. A mutation to the NF1 gene can release that brake
and set in motion the runaway freight train of uncontrolled cell
division that results in tumors.
Over the years, Morrison's lab has developed specialized tools that
allow researchers to track and study neural crest stem cells, which
give rise to the peripheral nervous system—the vast network of nerves
that branch out from the brain and spinal cord. Neural crest stem
cells usually disappear before birth, once they've completed their
mission.
In the current study, Morrison-lab scientists Nancy Joseph and Jack
Mosher tried to determine if deleting the NF1 gene can somehow cause
neural crest stem cells to persist beyond birth and form
neurofibromas in mice.
The researchers studied seven mouse models that had various mutations
of the NF1 gene and other genes known to contribute to the formation
of neurofibromas and their cancerous counterparts, malignant
peripheral nerve sheath tumors.
"The surprise was that we didn't see neural crest stem cells persist
after birth in regions where the tumors formed, even with the NF1
deletions," Joseph said. "That argues against a stem cell origin."
The Morrison lab's study, when combined with work done in Zhu's lab,
led U-M researchers to conclude that Schwann cells, not neural crest
stem cells, proliferate to form the tumors.
In fact, Zhu and his colleagues were able to show that a specific
type of Schwann cell, called a non-myelinating Schwann cell, is the
likely source of potentially cancerous neurofibromas.
"One of the difficulties of NF1 is that it is hard to predict when
tumors will grow and which tumors will turn malignant. You don't want
to use a very aggressive therapy because some tumors will never
grow," said Zhu, an assistant professor of molecular medicine and
genetics at the U-M Medical School and a member of the U-M
Comprehensive Cancer Center.
In addition to pinning down the cell type, Zhu's lab determined how
non-myelinating Schwann cells start overmultiplying. They found that
nerve damage and inflammation were among the two earliest events in
tumor initiation.
"With this insight into the initiation of the disease, we can develop
strategies to prevent the tumors from forming," Zhu said.
http://www.physorg.
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StemCells subscribers may also be interested in these sites:
Children's Neurobiological Solutions
http://www.CNSfoundation.org/
Cord Blood Registry
http://www.CordBlood.com/at.cgi?a=150123
The CNS Healing Group
http://groups.yahoo.com/group/CNS_Healing
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