Salk Institute neuroscientists have
obtained the first evidence that specific genes
control how the cortex forms functional units
during development. The cortex is the most
recently evolved part of the mammalian brain and,
in humans, governs abstract reasoning and symbolic
thought.
The study, published in the current issue of
Science, sets the stage for eventually
understanding disorders of cortical development
such as cerebral palsy or schizophrenia.
"It's also the first genetic evidence to
address a long-standing dispute among
neuroscientists," said Dennis O'Leary, Salk
professor and senior author of the study. "Many in
the field thought that development of the cortex
was influenced solely by other parts of the brain,
but our work shows that genes within the cortex
itself play a fundamental role."
The study, which was conducted in mice, focused
on the genes Emx2 and Pax6. These genes are found
in humans, where they are suspected to play a role
in brain development similar to the one shown in
mice.
In the study, the researchers examined how the
cortex develops in mice in which one or the other
gene was selectively removed, or "knocked out."
"When one or the other gene is knocked out, the
functional areas of the cortex are affected
differently, some shrink and some expand," said
Kathie Bishop, a postdoctoral fellow in O'Leary's
laboratory and lead author of the study. "But the
areas that shrink or expand differ, depending on
which gene is missing."
The Emx2 gene is normally most active in the
back of the cortex, with its activity gradually
tapering off toward the front of the neocortex.
Pax6 activity follows the opposite pattern.
The back of the cortex is predominantly
specialized to process vision, whereas the front
of the cortex handles motor functions and controls
voluntary movement.
Removal of Emx2 caused the visual areas to
shrink and the motor areas to expand; removing
Pax6 had the opposite effects. The identity of
each functional area was determined by the
activities of region-specific genes and the neural
connections that it makes to other parts of the
brain.
"Our findings imply that Emx2 and Pax6 act in
opposing manners during normal development to
control how the cortex becomes specialized to
perform different functions," said O'Leary. "When
one is removed, the influence of the other is
enhanced.
"Both Emx2 and Pax6 operate by controlling a
cascade of other genes, which we are now in a
position to identify," he added. "Understanding
how these genes work together to build a
functional cortex should help provide the
necessary foundation for understanding and
correcting congenital disorders that involve the
cortex."
Contributing to the study was Guy Gadreau at
the Max-Planck Institute for Biological Chemistry
in Göttingen, Germany.
The study, titled "Regulation of area identity
in the mammalian neocortex by Emx2 and Pax6," was
supported by the National Institutes of Health and
the Max-Planck Society. Bishop is supported by a
fellowship from the Natural Sciences and
Engineering Research Council of Canada.
The Salk Institute for Biological Studies,
located in La Jolla, Calif., is an independent
nonprofit institution dedicated to fundamental
discoveries in the life sciences, the improvement
of human health and conditions, and the training
of future generations of researchers. The
Institute was founded in 1960 by Jonas Salk, M.D.,
with a gift of land from the City of San Diego and
the financial support of the March of Dimes Birth
Defects Foundation. - By Suzanne Clancy
Related website:
The Salk
Institute for Biological Studies
[Contact: Suzanne Clancy,
Warren
Froelich]
14-Apr-2000