Energy-starved mice hint at preemie woes.

Like lightbulbs, genes turn on and off throughout an organism's life. Acting as genetic light switches are proteins known as transcription factors, many of which physically latch onto DNA to exert their influence.

Researchers from Baylor College of Medicine in Houston have now created mice bereft of one such transcription factor, a DNA-binding protein called C/EBP-alpha. These mice normally die within hours of birth, apparently starved for energy. Furthermore, the troubles confronting these "C/EBP-alpha knockout" mice, so named because of the inactivation of the transcription factor's gene, may provide a clue to the challenges facing premature infants.

Investigators have studied C/EBP-alpha for almost a decade. It belongs to a family of DNA-binding proteins, each of which activates a medley of genes. Although present in tissues as varied as lung and brain, C/EBP-alpha abounds most in the liver and adipose tissue.

Researchers quickly picked up on the latter two's functional similarity: both store energy. While fat cells accumulate in the adipose tissue, the liver stores glycogen, an energy-rich molecule formed from blood sugar. This suggested that C/EBP-alpha plays a role in energy metabolism, says M. Daniel Lane of Johns Hopkins University School of Medicine in Baltimore. Studying cultured cells, he and others added to that suspicion, demonstrating that C/EBP-alpha facilitates fat cell formation and activates a number of energy-related genes.

Since test tube experiments don't always reflect the complexity of a living organism, researchers hoping to confirm the protein's role needed to study it in an animal, explains Gretchen J. Darlington, who led the Baylor team that created the C/EBP-alpha knockout mice.

At birth, she says, these genetically engineered animals look identical to normal mice. But the knockouts soon become lethargic and die within 8 hours, Darlington and her colleagues report in the Aug. 25 Science.

Examination showed that blood-sugar concentrations in the knockout mice begin falling shortly after birth and that the livers of these animals store almost no glycogen. As a result, "Our animals get so weak they don't even feed," observes Darlington.

Through glucose injections into the mice, the Baylor team was able to provide the infant mice with enough energy to feed, but the animals remained unable to utilize nutrients or energy-rich fat from their mother's milk. As a result, even glucose-injected mice do not survive much beyond one day.

These problems arise because C/EPB-alpha is not available to turn on crucial genes, including ones relevant to energy metabolism, says Darlington. For example, the Baylor group found that the knockout mice synthesized reduced amounts of a variety of proteins, some of them needed for the production of glucose or glycogen.

C/EPB-alpha's gene lies dormant until the end of gestation, when fetuses begin storing energy for the birthing process and afterwards, Darlington notes. And that's why the C/EPB-alpha deficit doesn't kill mouse fetuses; they obtain nutrients and glucose directly from the mother.

Many characteristics of the knockout mice--such as immature lungs, low body fat and low blood sugar--resemble problems of premature infants. That may be because these babies are born before their own C/EPB-alpha genes become active, suggests Darlington. As they more fully characterize the role of C/EPB-alpha, the Baylor researchers hope the information may one day allow physicians to compensate for the transcription factor's presumed absence in premature infants.