In the beginning  pg. 2

Nusse and colleagues soon determined that the two seemingly unrelated genes were homologs—genes similar in structure, function and evolutionary origin, and found throughout the animal kingdom. So the names (int-1 and wingless) were combined, and Wnt was born.

“I can imagine that they were thinking: ‘What in the world is this cancer protein doing in a Drosophila embryo?’” says Jessen. “It’s a classic example of the two worlds coming together.”

Wnt is probably best known for its involvement in one of the earliest aspects of development, the formation of the primary body axis.

“You have a ball of cells, and somehow this signal tells the ball of cells which parts form the head and which form the tail,” says Ethan Lee, M.D., Ph.D., assistant professor of Cell and Developmental Biology at Vanderbilt who studies the Wnt pathway in frog (Xenopus) embryos.

In 1989, Andrew McMahon, Ph.D., and Randall Moon, Ph.D., demonstrated that injection of the int-1 (Wnt-1) gene into Xenopus embryos induced the formation of a secondary axis, resulting in a two-headed tadpole.

“This was critical because it was the first biological assay for int/Wnt-1, and it linked a proto-oncogene to a developmental process,” he says.

This multipart pathway has a number of other developmental roles in patterning the brain, heart and limbs and possibly in stem cell differentiation. Additionally, mutations that activate the Wnt pathway have been linked to cancers of the colon, skin, blood, liver and several other tissues.

One of the strongest links between Wnt and cancer was revealed with the discovery that mutations in the APC (adenomatous polyposis coli) gene—a component of the Wnt pathway—were required for the initiation of colon tumors.

Researchers have already identified more than a dozen Wnt ligands (proteins that bind Wnt receptors and initiate signaling), and new components of the pathway are being cloned and added to the already complicated system at a rapid pace.

“It really looks like a mess,” Lee says. “I would say we are basically ‘stamp collecting’ right now, putting together a picture that is very complex.”

Finding the switch

To make sense of the overwhelming data on this pathway, Lee and colleagues developed a mathematical model to examine how the pathway is regulated. They found that a protein called axin may be the limiting factor.

“Based on the model, we can propose that controlling axin levels and its turnover is the major way by which the pathway can be regulated,” Lee says. “Perhaps that is the way the pathway can be turned on or off.

“Interestingly, the genes that this pathway turns on are classic examples of proto-oncogenes,” he says. Researchers believe that if they could find a way to selectively switch the pathway “off,” they could halt tumorigenesis.

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