Researchers at Johns Hopkins restored the normal growth of
specific nerve cells in the cerebellum of mouse models of
Down syndrome that were stunted by this genetic condition.
The cerebellum is the rear, lower part of the brain that
controls signals from the muscles to coordinate balance and
motor learning.
The finding is important, investigators say, because
the cells rescued by this treatment represent potential
targets for future therapy in human babies with Down
syndrome. And it suggests that similar success for other
DS-related disruptions of brain growth, such as occurs in
the hippocampus, could lead to additional treatments
— perhaps prenatally — that restore memory and
the ability to orient oneself in space.
Down syndrome is caused by an extra chromosome 21, a
condition called trisomy — a third copy of a
chromosome in addition to the normal two copies. Children
with DS have a variety of abnormalities, such as slowed
growth, abnormal facial features and mental retardation.
The brain is always small and has a greatly reduced number
of neurons.
A report on the Johns Hopkins work with trisomic mice,
led by Roger H. Reeves, professor in the
Department of
Physiology and the
McKusick-Nathans Institute for Genetic Medicine at
Johns Hopkins, appears in the Jan. 24 issue of the
Proceedings of the National Academy of Sciences.
Reeves and his team used an animal model of DS called
the Ts65Dn trisomic mouse to show that pre-nerve cells
called granule cell precursors, or GCP, fail to grow
correctly in response to stimulation by a natural
growth-triggering protein. This protein, called Sonic
hedgehog, or Shh, normally activates the so-called Hedgehog
pathway of signals in these cells. These signals stimulate
mitosis (cell division) and multiplication of the cells in
the growing, newborn brain, according to the
researchers.
The GCP originate near the surface of the cerebellum
and migrate deeper into the brain to form the internal
granule layer, or IGL, the researchers note. Therefore, the
team studied the growth of the cerebellum in Ts65Dn
trisomic mice at seven time points, beginning at birth, to
determine when GCP abnormalities first occurred. The IGL
was similar in both normal and Ts65Dn mice at birth but was
significantly reduced in the trisomic mice by day six after
birth.
Furthermore, the researchers found that the reduced
number of GCP in these mice compared to normal mice was not
due to cell death; rather, there were 21 percent fewer GCP
undergoing cell division in Ts65Dn mice. This suggested
that stimulating these cells might restore normal numbers
of GCP, Reeves said.
The Johns Hopkins team then showed in test tube
experiments that GCP from the brains of Ts65Dn mice had a
significantly lower response to increasing concentrations
of a potent form of Shh called ShhNp. That is, increasing
concentrations of ShhNp triggered increasing rates of
mitosis. Despite their lower response, trisomic cells did
show a dose response with increasing ShhNp
concentrations.
"The fact that trisomic GCP responded to stimulation
of their Hedgehog pathway even in a reduced way is
significant," said Reeves, the senior author of the PNAS
paper. "It suggested that these cells could be stimulated
to reach normal levels of cell division by artificially
increasing their exposure to Hedgehog growth factor."
Based on this initial discovery, the team injected
into newborn Ts65Dn mice a molecule that stimulates the
Hedgehog pathway to trigger cell growth. Treatment of the
trisomic mice with this molecule, called SAG 1.1, restored
both the numbers of GCP and the number of GCP cells
undergoing mitosis to levels seen in normal mice by six
days after birth.
"The normal mouse cerebellum attains about a third of
its adult size in the first week after birth," said Randall
J. Roper, a postdoctoral fellow in Reeves' laboratory and a
co-first author of the PNAS paper. "This is the time during
which SAG 1.1 treatment of Ts65Dn restored GCP populations
and the rate of mitosis of those cells," he said. "However,
further research is needed to determine if it's possible to
reverse the effects of trisomy in other parts of the DS
mouse."
The other authors of the Johns Hopkins paper are Laura
L. Baxter, Nidhi G. Saran, Donna K. Klinedinst and Philip
A. Beachy. Baxter is a co-first author of this paper and is
currently at the National Human Genome Research Institute
of the National Institutes of Health.