As old age begins to creep up on them, many people go to great lengths and expense to smooth away the telltale wrinkles from their skin. But there's one set of bodily wrinkles that sets in before birth and lasts a lifetime.

These are the deep grooves and furrows - gyri and sulci - that riddle the surface of the brain's cerebral cortex. It's this maze of brain-crumpled folds and wrinkles that set mankind apart from much of the animal kingdom. The cerebral cortex is the outermost layer of the brain. It handles the highest-order thoughts that allow humans to read, speak and solve problems.

"The largest structure in the brain," observed clinical and research neurologist Christopher Walsh, "the cerebral cortex, is the headquarters of our intellect, often called gray matter.' The large surface area of the cortex," he continued, "houses two-thirds of the brain's 100 billion neurons in a thin layer, only slightly thicker than an orange peel. In order for this expanded surface area to fit within the confines of the human skull," Walsh went on, "the cortex folds in on itself, resulting in a series of ridges and grooves that give the brain its wrinkled appearance. It's like crumpling a sheet of paper into a ball."

Walsh directs a laboratory focused on the cerebral cortex and associated human diseases at Harvard-affiliated Beth Israel-Deaconess Medical Center in Boston. He is senior author of a paper in today's Science, dated July 19, 2002, and titled: "Regulation of cerebral cortical size by control of cell cycle exit in neural precursors."

"Our finding reports how the cerebral cortex develops and [defines] the role of the beta-catenin protein in cortical growth," Walsh told BioWorld Today. "By regulating a single gene, beta-catenin, we could not only make the cerebral cortex of a transgenic mouse much bigger, but also cause it to form the folds and fissures that the smooth brain of the mouse does not usually have.

"It's the first hard test," he observed, "of a hypothesis that's been around for a decade - namely, that the way the cerebral cortex regulates its size is like controlling a switch that governs dividing cells. It makes them either continue to divide or stop dividing and instead differentiate into neurons. Normally, neurons don't divide. It doesn't cause the cells to divide any faster, and it doesn't block them altogether from becoming neurons. It just makes more of the cells wait a little while longer before causing that switch to grow them to fill the wrinkled cortex.

The Migration Of Beta-Catenin

"We focused on beta-catenin," Walsh recounted, "because it is normally expressed in the dividing cells, which give rise to the cortex, and expressed little or not at all in the cells that are becoming neurons. So we hypothesized that if we jolted this system into expressing more beta-catenin, it might force some of the cells that normally become neurons to keep on dividing instead. We did that by introducing a transgene into a mouse, so it would express a stabilized form of beta-catenin that was overactive.

"Beta-catenin is a protein that normally lives in the cytoplasm of the cell," Walsh explained, "and does many different things. But it's best known for forming part of the glue that holds the cells together. It basically hooks on right near the membrane of the cell, where it associates with some of the proteins that connect one cell to another, and helps organize those proteins, so that the cells form stable adherence junctions with each other. In other contexts, however, beta-catenin leaves the surface of the cell and migrates to its nucleus. There it can activate a bunch of other genes, by serving as a transcription factor. So it seems to help tell a cell how crowded it is. If the cell is very crowded, then most of the beta-catenin seems to stay near the surface. Crowded, well-organized tissue seems to stop dividing. And then when beta-catenin migrates to the nucleus, it tends to tell the cells to divide. But moving mutant beta-catenin into the nucleus sometimes means a tumor.

"To make our bulky-brained transgenic mice," Walsh went on, "the paper's first author, pathologist Anjen Chenn, introduced the mutant beta-catenin gene into the pronucleus of the mouse egg. There it became incorporated into the murine DNA and expressed protein just as though it were a normal gene. We looked a few days before the mice would normally be born - 21 days after the eggs were fertilized - and saw that their brain-wrinkled gyri and sulci were already formed. These are also visible in human embryos before birth."

When Walsh's transgenic mice matured, did their convoluted brains - hallmark of humans - have any influence on their behavior, or intellect?

"That's the $64,000 question," Walsh allowed. "But unfortunately," he continued, "we were so amazed that we had got these mice with such big brains that we didn't want to risk losing them by letting them grow up to be adults. So we just analyzed them right about the time of birth."

Giving Transgenic Mice A Swelled Head

"Chenn first looked where beta-catenin was in the developing cortex," Walsh recounted. "And we said, Aha! It's in the dividing cells, and there's a lot left of it after the cells divide. So maybe it's part of the switch that regulates the cell's division.' Then we said, Okay, if we boost the beta-catenin, maybe some of the cells that normally stop dividing will keep dividing.' So we boosted beta-catenin in this transgenic mouse and said, Whoa! That brain is huge. How did it get that way?' We favored the idea that it got that way by acting on this beta-catenin switch, because that is the governing hypothesis.

"Bigger brains are not always good for you," Walsh pointed out. "In some human disease states people have big brains but they're not always functional. There's a rare condition called megalencephaly, big cerebral cortex. It means the brain is very large but doesn't function properly, so the kids have terrible seizures. Now we are trying to tone down the transgene a little bit," Walsh concluded, "so we don't have such big brains, and we think the animals will survive better that way."