The formation of fingers and toes in mice depends on multiple, interlocking signaling pathways, researchers in this week's Science report. These linked pathways protect the process of digit formation from mutations that could make it go awry.

A team led by Rolf Zeller, a developmental biologist at the University of Basel in Switzerland, wanted to understand why the complicated business of limb formation in a developing embryo turns out okay most of the time.

Signaling in the mouse embryo limb bud Courtesy of AAAS/Science

Past work showed that in embryos, the germ layer that eventually forms the skin communicated with the one which transforms into connective tissue. Others had also teased out some of the molecular players in development: the proteins sonic hedgehog (SHH), gremlin (Grem), fibroblast growth factor (FGF), and bone morphogenic protein (BMP). However, it wasn't clear how all these chemicals interacted.

Zeller and his colleagues used gremlin-1 knockout mouse embryos, which normally have no digits in the paws and fused bones in the lower legs, to probe the role of each of these proteins in forming normal limbs. A computer model predicted the pathways that are essential in forming mouse digits. It also suggested that the entire system hinged on an initial spike in the molecule BMP4. By tweaking expression of BMP4 at different times, the researchers found a fast and slow feedback loop that together orchestrate limb development. A quick pulse of BMP4 jumpstarts gremlin-1 signaling within two hours, and the increase in gremlin in turn lowers the levels of BMP4. The initial spike in gremlin-1 and drop in BMP4, however, spurs the slower sonic hedgehog signaling pathway. Sonic hedgehog, in turn, boosts gremlin-1 levels. Sonic hedgehog can then direct the formation of digits in the embryo.

The study was "very thorough," said Cheryll Tickle, a developmental biologist at the University of Bath in England, who was not involved in the work. "The computer-aided simulation of activity is also something that's fairly novel in the field," she said.

Susan Mackem, a developmental biologist at the National Cancer Institute in Bethesda, MD., also thought the computer model provided valuable insight. For instance, the model predicted the critical role of BMP in very early stages of limb development, she said. "And, in fact, they were able to go back and show this genetically."

In the future, Zeller said, they may investigate "whether this signaling pathway is something that's limb specific, or do mechanisms like this play a role in patterning other structures or organs?"


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