By outfitting mice with a chunk of DNA that directs wing development in bats, scientists have created rodents with abnormally long forelimbs, mimicking one of the steps in the evolution of the bat wing. Their work gives weight to the idea that variations in how genes are controlled, and not just mutations in the coding regions of genes, are a driving force in evolution.
The slightly longer forelimbs of the transgenic mice “make them more batlike,” says Nipam Patel, a professor of molecular and cell biology and integrative biology at the University of California, Berkeley, who was not involved in the work. “It seems like a subtle difference, but evolution works by these subtle differences.”
The researchers focused on a gene, Prx1, that plays a part in the elongation of limb bones in mammals. The gene’s expression is regulated by another sequence of DNA, called a Prx1 enhancer. To investigate how the enhancer shapes limb development, Richard Behringer, a professor of molecular genetics at the University of Texas MD Anderson Cancer Center, and his colleagues around the country put the bat version of the Prx1 enhancer into mice so that it controlled the mouse Prx1 gene. These transgenic animals developed forelimbs that were on average 6 percent longer than normal by the time they were born. It was a significant difference, although “the mice look like mice,” Behringer says. “They’re not going to fly out of the cage.” The researchers report their work in the latest issue of Genes and Development.
To have any chance of flying, mice would have to develop very different forelimbs, like those of bats, which are longer and have membranes stretched between the bones. Behringer says that he’d like to try replacing the limb enhancers in mice with those from other animals, such as whales or wallabies.
Charles Darwin contemplated the evolution of different kinds of limbs in On the Origin of Species. Starting with a basic limb pattern, “successive slight modifications,” he wrote, eventually produce the various mammal limbs we see today: human hands, bat wings, whale fins.
“We think what we’ve done is made one of those slight modifications,” Behringer says. “Maybe during evolution you’d have a lot of those and the limb would get a lot longer, and maybe some of the tissue would be retained between digits, ultimately leading to the structures that would allow a bat to fly.”
“It’s a very nice demonstration of something that people have been suspecting now for some time: that regulatory sequences rather than changes in protein sequences sort of drive evolution,” says Susan Mackem, who heads the Developmental Biology Unit at the National Cancer Institute’s Center for Cancer Research. Mackem was not involved in Behringer’s research.
Behringer’s team also found something unexpected. When the researchers created mutant mice that lacked the mouse Prx1 enhancer, the animals developed forelegs of a normal length. That suggests that more than one enhancer controls the expression of the Prx-1 gene in mice, ensuring what Behringer calls a “regulatory redundancy.”
“As long as there is one copy to do the work, the other copy can be creative,” says Ann Burke, an associate professor of biology at Wesleyan University.