The First Gasp

After popping through the birth canal and into the bright lights, babies must start breathing on their own. Before that first piercing scream, a complex genetic signaling has spent weeks getting ready for the first gulp of air. Now, scientists have finally identified the taskmaster that switches on the cellular players. Eventually, the results could help both premature babies and sick adults.

About a month before birth, the lungs of human babies prepare themselves for the outside world. In one of the final and most crucial steps of this preparation, the lungs begin making surfactant proteins that decrease the surface tension of the lungs' mucus lining, which is necessary to prevent the lungs from collapsing when filled with air. The new study finds that a gene called Foxa2 is the signal that sets this process in motion.

Researchers have suspected for about a decade that Foxa2 turns on surfactant genes, but they couldn't test this in animals because any mutations that knocked out Foxa2 killed the embryos too early in development. So neonatalogist Jeffrey Whitsett at Cincinnati Children's Hospital Medical Center, Ohio, and colleagues devised a way to turn the Foxa2 gene off in mouse lungs after the fetal mice had mostly developed but before their lungs fully matured. These newborn mice had trouble breathing after birth, and died within 12 hours. Autopsies revealed immature lungs and lack of surfactants.

The team then measured the expression of about 22,000 genes and found 55 genes that turned either on or off in Foxa2's presence, they report online this week in the Proceedings of the National Academy of Sciences. Turned on genes included those that produced the surfactants and fats that reduce surface tension, as well as infection fighting compounds. "Foxa2 turns out to regulate all the 'I'm going to be born' genes," says Whitsett.

"Ultimately, the finding could lead to more precise therapies for preterm babies," says neonatalogist Samuel Hawgood of the University of California, San Francisco. Babies born more than a month prematurely go into respiratory distress within a few hours after birth if they're not given artificial surfactants. If Fox2a has the same effect in humans and researchers can learn what flips the switch, Hawgood says, "then there may be possible pharmacological approaches to activating it at will." Such therapies could also help with diseases that affect the lungs, such as pneumonia, Whitsett adds.

Related Sites
More about preterm babies from the NIH
More about respiratory distress