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Hints from Wnts
by Paul Muhlrad
The secret to rebuilding body parts might be found in a fish fin.
One day after trimming the edges of a zebrafish tail fin (left), things look a little too neat. Never fear: by ten days post amputation, the tail fin has regenerated.
When it comes to replenishing lost body parts, some of our distant cousins can teach humans a thing or two. Zebrafish, for example, have no problem regenerating perfect tailfins after being nipped by an aquarium mate—or snipped by an inquisitive doctoral student, like the University of Washington's Cristi Stoick-Cooper.
She and her colleagues in the laboratory of HHMI investigator Randall T. Moon recently coaxed a few secrets from zebrafish on how they regrow their tails. Specifically, the researchers discovered a critical ingredient in the creatures' regeneration potion—a group of signaling molecules called Wnt proteins (pronounced "wint"). Although Wnts are well-known regulators of many cellular processes, their role in organ regeneration had never been examined.
Wnt proteins typically respond to extracellular signals by prompting another protein, called ß-catenin, to enter the nucleus and activate specific genes. In particular, Stoick-Cooper, University of Washington postdoc Gilbert Weidinger (now at the Technical University of Dresden), and colleagues found that Wnt/ß-catenin activity rises in zebrafish undergoing tailfin regeneration, but the fish were unable to regrow snipped tailfins when researchers disabled the Wnt/ß-catenin pathway. Zebrafish engineered with elevated Wnt signaling levels regenerated their tailfins with added haste.
Surprisingly, zebrafish that overproduced a different Wnt—Wnt5b—failed to regenerate tailfins altogether, but mutant fish lacking a functional Wnt5b gene replaced their tailfins at an accelerated pace, indicating that this Wnt protein normally inhibits regeneration.
These experiments, reported in the February 1, 2007, issue of Development, reveal that Wnts are central to the regeneration process in zebrafish, says Moon. Moreover, he cites his team's observation that Wnt activity in mice increases during liver regeneration, suggesting that the same pathways may be at work—and potentially extendable—in mammals. "Manipulating Wnt signaling could hold the key to regenerating damaged organs or limbs in humans," says Stoick-Cooper. "It's just a dream right now, but we're getting closer to understanding how this might be possible."
Photo: Moon lab