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Protein Linked to Embryonic Brain Development

Could provide clues to some birth defects, says study

THURSDAY, Sept. 20, 2001 (HealthDayNews) -- A single protein may play a key role in the development of the cerebral cortex, the outer layer of the brain that's considered the seat of human intelligence, says new research.

Using mice, University of Chicago neurobiologists describe the first evidence that a protein known to control formation of limbs and other body systems before birth also appears to determine how the cerebral cortex develops in an embryo.

The researchers say the finding, reported today in the online version Science, has implications for the understanding how human embryos develop from a very simple egg to a complex organism.

Senior study author Elizabeth Grove, assistant professor of neurobiology, pharmacology and physiology, says scientists have known that embryos set up several signaling centers that send out proteins to tell nearby tissues how to develop, for example, a hand.

But she says little was known about the function of these centers in the development of the cerebral cortex, the area of the brain responsible for higher brain functions such as vision, memory and sensation.

The discovery that the genes that carry instructions for proteins involved in embryonic patterning also exist in the embryonic cerebral cortex made Grove and colleague Tomomi Fukuchi-Shimogori wonder whether the proteins had a similar organizational effect in the brain.

"But it was very, very difficult to discover what [the proteins] were doing, because it was difficult to manipulate them," says Grove.

She says Fukuchi-Shimogori developed the solution: a microsurgical technique that could introduce the genes for one protein, fibroblast growth factor 8 (FGF8), into the cortices of living mouse embryos. FGF8 normally is released from a center at the front of the embryonic cerebral cortex. Grove says it appears to be crucial to laying down the three-dimensional blueprint for the developing cerebral cortex.

Using the new technique, the researchers increased the amount of FGF8 produced in one group of mice while decreasing the levels in others. Then they manipulated the cortices of another group of mice to create a second FGF8-producing center near the back of the cerebral cortex.

The mice, which were treated about halfway through gestation, continued to develop and were born normally. Later, the researchers euthanized the animals to examine their brains.

They found that when FGF8 levels were increased, surroundings areas of the cortex grew while those farther away shrank. Reducing the levels of FGF8 had the opposite effect.

But Grove was most excited by what happened to mice given a second FGF8 center. They developed duplicate areas of the cortex, including the region responsible for sensation, something she says has never been accomplished before in a laboratory.

"This molecule is very important in telling the embryonic cortex what kind of functions it's going to be devoted to," says Grove. FGF8 probably triggers a cascade of other proteins that direct the development of these brain structures, she says.

"It also might hint at how new areas could be added in evolution" and may reveal how simpler brains adapted to add new areas and new capabilities, she says. "That's always been a great puzzle."

Dr. Pasko Rakic, chairman of neurobiology at Yale University Medical School, calls the study "experimentally sophisticated." He says the appearance of the duplicate region is important because it mimics how new brain regions appeared during evolution.

The researchers now are trying to find out if a duplicate touch area that they generated in the mouse cortex is functional. Grove says she doesn't know how that might effect the animals' sensation of touch.

Rakic says it may not mean the animals had enhanced sensory abilities. "In evolution, changes occur over millions of years, until one is good. … It's not likely that the first change that one produces is better for the mouse," he says.

Because the animals were euthanized, it was not clear whether the animals were physiologically different. Grove says they behaved normally, but future studies will examine their behavior in more detail to determine if the manipulation had other effects.

Grove and Rakic say the findings may have important implications for human health. "There are lots of birth defects that involve mispatterning," says Grove.

"The more we know about how the body and the brain normally organize themselves, the more we'll understand these different disorders and diseases that lead to birth defects," she says.

Certain compounds that cause birth defects target molecules like FGF8, and the study's findings could improve the understanding of these potentially harmful interactions, she says.

SOURCES: Interviews with Elizabeth A. Grove, Ph.D., assistant professor, Department of Neurobiology, Pharmacology and Physiology, University of Chicago, and Pasko Rakic, M.D., Ph.D., professor and chairman, Section of Neurobiology, Yale University School of Medicine, New Haven, Conn.; Sept. 20, 2001, Science
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