Molecular mechanism is key in brain development

Elizabeth Grove, Assistant Professor in Neurobiology, Pharmacology & Physiology, and Tomomi Fukuchi-Shimogori, a postdoctoral fellow, have discovered a molecular mechanism associated with brain development.

Evidence that specific locations in the brain control complex tasks has existed for a long time. Head injuries associated with damage to very specific areas result in the loss of very specific functions such as speech, the ability to see color or to recognize objects by their names, for example.

In the cerebral cortex, or outer layer of the brain, specific functions, including vision, touch and memory, are laid out like a map.

For the first time, University researchers have discovered a simple molecular mechanism that connects the development of these special areas within the brain with the development of an embryo. Their discovery suggests how simple brains evolve into more complex ones. Elizabeth Grove, Assistant Professor in Neurobiology, Pharmacology & Physiology, and Tomomi Fukuchi-Shimogori, a postdoctoral fellow in her lab, have published their findings in a paper that appears on Science Express, Science magazineís Web site for new research.

Because specific areas of the cerebral cortex can only be seen after birth, it has been impossible until now to determine the molecular mechanisms responsible for forming them in the embryo.

“We knew that signaling proteins associated with patterning other parts of the body were found in the embryo cortex, but we did not have an easy way to find out what they were doing there,” said Grove. “There has been some speculation that cortical patterning depended on completely unique mechanisms.”

The researchers found that manipulating one of the signaling proteins in a developing mouse brain causes radical changes in the brain cortex.

Fukuchi-Shimogori developed a microsurgical technique that allows her to insert genes into the cortex of mice while they are still in utero, about halfway through gestation. The mice are born normally and can be analyzed at any age.

FGF8, or Fibroblast Growth Factor 8, a member of a family of signaling proteins involved in forming other structures in the embryo, is normally found near the front of the developing cortex. Using Fukuchi-Shimogoriís technique, the researchers were able to manipulate the amount and position of this signaling protein in the embryo and look for changes in the cortical pattern much later.

They increased the amount of the signaling protein in its normal position, decreased it by inserting a gene for a receptor able to soak up the protein or expressed it in a new position. Each manipulation profoundly affected cortical area patterning.

“We found very strong evidence that this signaling protein directs the development of the cortex,” said Fukuchi-Shimogori.

With increased expression of this protein, the sizes and locations of the areas changed. Areas that are toward the front of the cortex and closer to the source of the molecule were enlarged at the expense of areas further away from the source. Reducing the signaling protein caused shifts in the opposite direction.

“Most dramatic, when a new source of the signaling protein was generated close to the back of the embryonic cortex, the whole program changed,” said Grove. “Now, a region near the back of the cortex was reprogrammed to form a duplicate of a more central region, a second touch area. We saw an identical array of patches that correspond on a one-to-one basis with the mouseís whiskers.”

Creating this whole new cortical area by manipulating one molecule has not been done before and may provide a clue about how the cerebral cortex changes in evolution. More functionally complex brains seem to evolve by adding new areas to the cortex.

“We have had no idea how evolution achieved this kind of change,” said Grove. “So it is exciting to find that you can add a new area by modifying signaling by a single protein.”