When Mice Fly: Bat DNA leads to longer limbs in mouse embryos

Give a mouse embryo a stretch of bat DNA, and its limbs grow a little longer, a new genetic study shows. The change, though small, may illustrate one evolutionary step on the path to wings.

Charles Darwin suggested that a series of such minor changes would be key to building new body features, like wings, from old ones. “If you have lots of these changes over time—and with natural selection—ultimately you’ll end up with some structure like a bat wing,” says study leader Richard Behringer, a developmental biologist at the University of Texas M.D. Anderson Cancer Center in Houston.

To support this idea, Behringer’s team examined a gene called Prx1 that controls bone growth by turning on other genes. Lab mouse embryos missing the gene grow puny limbs and misshapen heads, and pups die at birth. A short stretch of DNA near, but not part of, Prx1 enhances its activation, helping a cell control how much of the gene’s protein gets made.

The short-tailed fruit bat, with wings analogous to the front legs of mice, has a virtually identical version of Prx1. However, the enhancing stretch of DNA varies greatly between bats and mice, which are separated by 80 million to 100 million years of evolution. To test the effects of this difference, Behringer’s team spliced the bat version of the enhancer into normal lab mice. In the limb bones of the mutant mice, Prx1 was 70 percent more active than in unaltered mice.

More striking, the mutant embryo limbs grew slightly longer than those of normal mice, when measured a couple of days before birth. The difference in forearm length was just 6 percent—a few tenths of a millimeter—but appeared consistently in dozens of mice, says Behringer, whose team reports its findings in the Jan. 15 Genes and Development. The cells that make bone also divided slightly faster in the mice with the bat DNA. Six weeks after birth, however, the forearms of both kinds of mice had become similar in length, possibly due to differences in mouse size at birth and later variations in eating habits.

Boosting Prx1 gene activity isn’t the whole story, Behringer cautions. When his team engineered mice that lacked this gene-enhancing sequence, the mouse limbs grew normally, indicating that other enhancers, as well as multiple genes, play a role in limb growth. “One gene change is not going to have a mouse flying out of the cage,” he says.

This redundancy makes sense because dramatic changes in body shape could spell disaster for an animal, says Susan Mackem of the National Cancer Institute in Bethesda, Md. By tweaking the expression of genes that control limb growth “you can play around with things without totally compromising development,” she says.

Behringer isn’t stopping with fruit bats. He plans to use the lab mouse as a test bed for the effects of gene enhancers from other animals, such as whales and wallabies.