July 19, 2002
Protein Regulates Growth of the Cerebral Cortex
A protein that escalates the rate of growth of the cerebral cortex
in young mice may help scientists explain how changes in a relatively
small number of genes that regulate neural development may have
contributed to increases in the size of the brains of higher
mammals.
In an article published in the July 19, 2002, issue of the journal
Science, HHMI physician postdoctoral fellow Anjen Chenn and
Christopher A. Walsh at Beth Israel Deaconess Medical Center and
Harvard Medical School reported that the cerebral cortex of transgenic
mice bearing an altered form of the protein β-catenin expanded
horizontally in area but not in thickness. These changes produced
characteristic crests and grooves, called gyri and sulci, which
anatomically distinguish human brains from those of lower animals. The
cerebral cortex is the region of the brain responsible for higher
intellectual functioning.
“We saw that the brains of these mice were greatly increased in size so that, compared to normal mice, their brains at a particular age were about two- to three-fold increased in volume.”
Christopher A. Walsh
“It has long been known that during evolution, the size of the
cerebral cortex expanded disproportionately relative to the rest of the
brain,” said Chenn. “But not very much was known about the
developmental mechanism underlying that expansion. One theory is that
the number of progenitor cells increased during evolution, and these
cells gave rise to neurons that made up a greater number of repeating
functional units called cortical columns.” According to this
theory, said Chenn, the greater number of progenitor cells might result
from immature cells that continue to divide to produce even more
progenitor cells, before ultimately “committing” to develop
into neurons.
Chenn and Walsh theorized that β-catenin might be responsible
for regulating the proliferation of progenitor cells because it is
known to control cell growth and it has been implicated in the growth
of specific brain tumors. An additional piece of evidence emerged from
Chenn and Walsh’s experiments which showed that β-catenin is
present at junctions between progenitor cells, in the embryonic
epithelium, where a protein that regulates cell division would be
expected to be located.
“We found that beta-catenin was expressed in the right cells
at the right time and the right place,” said Chenn. “So,
that led us to ask the question of whether it was actually regulating
cell division and differentiation.”
To understand β-catenin's role in regulating neural growth, the
scientists generated transgenic mice with an altered β-catenin
gene that produced a protein that was resistant to the normal
degradation that regulates levels of the protein. “We saw that
the brains of these mice were greatly increased in size so that,
compared to normal mice, their brains at a particular age were about
two- to three-fold increased in volume,” said Chenn. “And
the striking thing about these brains was that when we made sections
through them, we observed that the increase in brain size was not due
to an increase in thickness of the cerebral cortex but an increase in
its surface area of the cortex. The cortex had expanded so much in
surface area that it began to fold in on itself and generate the
grooves and bumps that are reminiscent of the sulci and gyri in higher
animals.”
Chenn and Walsh next investigated why the mice developed larger
brains. They knew that there were at least three possible explanations:
the increase could have been due to faster cell division; it could have
been caused by a reduction in normal programmed cell death — called
apoptosis — that occurs during brain development; or because an
increase in the number of progenitor cells continued to multiply before
maturing.
Their detailed studies of the brain cells of the transgenic mice
confirmed that the increase in brain size was caused by the
over-production of progenitor cells. “This study is important
because it gives us a better understanding of how beta-catenin works by
regulating the decision of cells to either keep dividing or stop
dividing,” said Walsh. “And secondly, the study shows how,
with a simple metabolic switch, nature might be able to shift to a
larger cerebral cortical size, but still maintain relatively normal
architecture.”
Chenn emphasized, however, that it remains uncertain whether the
increased cortical size would result in enhanced intelligence.
“Without doing true functional studies, we cannot really conclude
that these mice function at a higher neurological level,” he
said. “However, we did look at the expression of a variety of
markers of cell differentiation. From these studies, we can say that
the pattern of distribution of the expression of these markers is
preserved in the transgenic animals. So, their brain tissue is not
disordered like a tumor, and, in fact, maintains a relatively ordered
pattern of differentiation.”
Although the pattern of cellular differentiation appeared normal,
“these animals are not healthy,” Chenn said. “They
don't live past birth, and we're not sure why. So, this is only the
first step in understanding how brain size can be increased. We are
certain that the increase in brain size over evolution is going to be
more complicated than just changes in one gene.” The major
scientific significance reported in the article, said Chenn, is the
discovery that the embryonic epithelium plays a role in cell
differentiation.
According to Walsh, their findings pose some interesting questions
for further study. “We would like to determine whether
beta-catenin actually does regulate the size of the cerebral cortex, by
analyzing the protein in different species with different sized
cortexes. Also, we could explore whether there are mutations in
beta-catenin associated with human diseases in which the cerebral
cortex is either too big or too small – respectively
megalencephaly known as and microcephaly.”
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