How do you make a mountain out of a mole hill?

That's what Harvard Medical School (HMS) Assistant Professor of Pathology Li-Huei Tsai has been trying to find out in her studies of brain development.

To date, it remains a mystery to scientists how a few cells differentiate to form the billions of cells and connections which make up the brain.

"This area is entirely a black box," Tsai says.

But a new form of mutant mouse engineered by Tsai and her colleagues at HMS is starting to unravel what is considered to be one of the greatest enigmas in biology.

Tsai and her team have recently isolated a gene in mice, called p35, which appears to play an integral part in the formation of the cortex.

To elucidate the gene's effects, Tsai used a recently-developed technique which allows researchers to selectively create "knockout mice"--mutant mice who are lacking in a specific gene. The researchers can then study the effect the loss has on the mutants by recovering the excited gene for study.

The technique is said to be invaluable in studying genetics.

The p35 mutants, which were seemingly normal at first, became consistently abnormal when grown.

Tsai says the mice lacking the gene were "not as active," were uncoordinated and walked unsteadily. Although they were still fertile, the mothers "displayed nurturing defects."

But most importantly, Tais says, the mice "were especially sensitive to suffering fatal seizures."

When the mutants' brains were sectioned and inspected, Tsai found that "the cortex [was] pretty much messed up."

Instead of the cells' elegantly moving into their correct spots, the process seemed to proceed in the dark, with cells going to the wrong places and inadvertently bumping into each other.

When finished, the normal six layers which should be present in the cortex were absent and "the distribution of cells seemed random at first," Tsai says.

The precise nature of the disruption gradually came to light. The mutation seemingly altered the genetic "sign posts" which allow the cells to orient themselves and travel to the correct places.