Gene makes fetal skin become watertight.

While growing in a fluid-filled womb, safe from most infectious microbes, a fetus has little need for a protective coating. Yet the outside world is a far drier and more dangerous place. About a month before it's due, a human baby prepares for its new environs by transforming its skin into a watertight barrier that also keeps out bacteria and viruses.

By disabling a single mouse gene, scientists have now created a strain of mice unable to develop such a life-preserving skin barrier. Study of the animals, which die less than a day after birth from shock brought on by rapid dehydration, should help investigators identify other genes that play a role in barrier formation.

The mutant mice may also point the way toward drugs to help human infants born months before this crucial shield takes effect. These premature babies face a high risk of infection and dangerous weight loss due to dehydration.

"If you could pharmacologically intervene and accelerate [skin-barrier formation], you could improve survival," says dermatologist Dennis Roop of Baylor College of Medicine in Houston.

Scientists compare the skin barrier to bricks and mortar. The bricks, nearly indestructible aggregates of protein, collectively form a scaffold called the cornified envelope. Cells in the uppermost layer of skin create this envelope as they die. Lipids, which are fatty molecules, then provide the mortar that fills the spaces in the scaffold.

The gene for a protein called Klf4 appears to serve as a switch that turns on barrier formation, Julia A. Segre, Christoph Bauer, and Elaine Fuchs, all of the Howard Hughes Medical Institute at the University of Chicago, report in the August NATURE GENETICS. Klf4 belongs to a family of DNA-binding proteins, each of which regulates a different set of genes.

Investigators knew that the gene for Klf4 is extremely active in maturing skin cells, but they didn't know the protein's exact function. The Chicago team addressed that issue by creating mice that have a mutation in the Klf4 gene.

The resulting newborns looked normal, but all died within 15 hours of birth. The researchers observed that the pups failed to feed, but that didn't explain their early deaths because newborn mice can survive for a full day without feeding.

Suspicious that the mutant mice had a defective skin barrier, the researchers dipped the animals and normal newborn pups in a blue dye. The dye barely stained the normal mice but suffused the newborns lacking Klf4, a sign that the skin barrier was absent in those rodents.

By measuring the skin's ability to conduct an electrical current, which increases with the amount of water in the tissue, Segre and her colleagues showed that the mutant mice were losing significant amounts of water through their skin. In people, a similarly dramatic loss of water would lead to kidney shutdown, shock, and ultimately death.

Beginning their search for genes regulated by Klf4, the investigators have already found three that encode proteins of the cornified envelope. In the mutant mice, these genes are abnormally active, leading to the formation of a distorted envelope.

The investigators now hope to use the rodents to identify drugs that can trigger skin-barrier formation in fetuses and newborns. Today, physicians have few options. They can prescribe potentially harmful growth-stimulating hormones to women they suspect will deliver prematurely or, after a baby is born early, place the infant in a humidified incubator and slather its skin with Vaseline.