Previously, other investigators have found that mice harboring mutations in Wnt inhibitor genes often exhibit severely truncated forebrains. So the group asked whether loss of the dominant negative Tcf7l2 would perturb head formation. To test that they injected frog embryos with a short inhibitory RNA designed to artificially degrade the frog version of truncated Tcf7l2.
The resulting embryos were essentially headless, showing complete loss of structures in front of the midbrain, the very point where Wnt signaling is brought to a grinding halt in normal mouse or frog embryos by the opposing ventral morphogen sonic hedgehog and its henchman Vax. This is the first study to provide an explanation for how this molecular line in the sand is drawn.
"Our results illustrate a very basic principle-that if you have the power to turn something on, you must have the ability to turn it off. Otherwise, you set up a situation of uncontrolled signaling," says Lemke.
The disastrous outcome of uncontrolled signaling is also illustrated by the fact that cancer cells often show aberrant reactivation of factors governing normal development. Some colon cancer tumors, for example, show high levels of Tcf7l2's partner -catenin and resulting unchecked Wnt signaling causes the disease. More intriguingly, the inability of tumor cells to make a short, inhibitory form of a factor related to Tcf7l2 is also associated with tumorigenicity.
"So Wnts and sonic hedgehog may be in competition in colon cancer just like they are in the brain," Lemke says. "Our work could provide insight into how that happens mechanistically. "
|Contact: Andy Hoang|