April 13, 2000
La Jolla, CA – 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.