"More research is needed before scientists will even know whether manipulating ß-catenin and the Wnt pathway in skin might be a feasible treatment for hair loss," says Elaine Fuchs.
Photo: Mark Segal
o test the theory that ß-catenin has a role in hair follicle development, Uri Gat, an HHMI associate in Fuchs' lab, created a strain of mice that carries an extra copy of the ß-catenin gene. This wasn't an ordinary ß-catenin gene; instead, it coded for a stabilized variant of the protein, known as the constitutive form, which resists normal degradation. In essence, this alteration in ß-catenin mimics the effect of permanently turning on a Wnt signal in the skin.
"By expressing this constitutive form of ß-catenin, the [mature skin] cells acted as if they were embryonic skin cells, or stem cells," says Fuchs. "They started to produce hair follicles in many places over the skin surface where normally we wouldn't see those follicles."
The new hair follicles began to appear on the mice within a month after birth, filling in the spaces between existing follicles. Hair did not form, however, on the footpads or on other naturally hairless areas. Apparently, only transgenic skin already primed for hair growth could be induced to create new follicles.
As hoped, Fuchs' super-furry mice did shed new light on why some embryonic skin cells become epidermis and others develop into hair follicles. The key appears to be the cell's ability to receive a Wnt signal. "We effectively made the adult skin cells act as if they were receiving a Wnt signal and showed that they behaved like embryonic skin cells or so-called stem cells," Fuchs says. "We therefore postulate that a distinguishing quality of a skin stem cell may be its ability to receive and respond to a Wnt signal."
Unlike embryonic cells, however, the skin of the transgenic mice produced an endless supply of ß-catenin. This overabundance created some unwanted side effects. The mice had thicker-than-normal skin, which developed into ridges around their ears, eyelids, and nose, and benign tumors began to form in the new follicles. Their hind paws also were three times larger than normal. "This is an example of how too much of a good thing can lead to a bad thing," says Fuchs.
For scientists interested in tumor development, however, some of the side effects had a silver lining. Two types of benign tumors, trichofolliculomas and pilomatricomas, showed up in the mice. Both are rare in mice, but pilomatricomas in particular are relatively common in humans. These noncancerous lesions appear as small, sometimes bluish bumps on the skin. "Little was known about their origins before we began the studies," says Fuchs. "But now we know that the tumors are definitely coming from the hair matrix, the transiently dividing precursor cells that express Lef-1 and that differentiate to form the hair shaft. Our research also suggests that defects in the Wnt pathway are involved in the formation of these types of tumors in humans." Fuchs and her colleagues are now investigating this theory.
Fuchs notes that more research is needed before scientists will even know whether manipulating ß-catenin and the Wnt pathway in skin might be a feasible treatment for certain types of hair loss. Scientists need to find a factor that can stabilize the natural ß-catenin within skin cells just long enough for new follicles to form—but not so long that the skin thickens and develops tumors. At the same time, researchers must find ways to induce the expression of Lef-1 so that it can bind the stabilized ß-catenin in order to create new hair.
If there are to be practical benefits of this research, the first is likely to be woollier sheep rather than hairier middle-aged men, Fuchs says. It should be possible, she says, to genetically engineer sheep in a way that allows controlled activation of transgenic ß-catenin. The research may also propose a way to stop unwanted hair growth by inhibiting ß-catenin and the Wnt pathway.
