Elaine Fuchs and HHMI associate Uri Gat created a strain of mice that produced hair follicles in many places on the skin surface where such follicles would not normally appear.
Photo: Mark Segal
ntil now, researchers thought that hair follicles form only during embryonic development. This would mean that each individual is born with a fixed number of hair follicles. The average human head, for example, has about 100,000 hair follicles spread across the scalp. Each follicle in a developing embryo receives a reservoir of stem cells that are capable of differentiating to produce hairs. But that doesn't guarantee a lifetime of luxuriant hair growth. In some men and women, follicles shrink, or "miniaturize," with age, churning out shorter and fewer hairs. This can eventually lead to inactivation of the hair follicles and subsequent hair loss. In male and female pattern baldness, or androgenic alopecia, a combination of genetic and hormonal alterations can elicit this response.
Men with androgenic alopecia might begin to notice hair loss as early as their teens. The thinning tends to follow a characteristic pattern: the hairline recedes first from the forehead and temples and then from the crown of the head. Women are usually in their forties or older before any permanent hair loss begins, and the thinning is much more diffuse than in men. Scientists aren't sure exactly why some people's hair follicles miniaturize, but they suspect a genetic influence because androgenic alopecia runs in families.
With no new follicles forming after birth, current treatments for various types of hair loss require the presence of active follicles—sometimes installed by surgical transplantation. That may change in light of Fuchs' new findings, however, which showed that, contrary to previous assumptions, it is possible to generate new follicles in adult skin and to reactivate miniaturized ones. The key is to induce certain proteins, most notably ß-catenin, to accumulate in the adult skin cells. The mice that Fuchs' team studied not only grew hair out of existing cycling follicles, but also formed entirely new follicles from scratch between the existing follicles. The result? Super-furry mice.
The story of these special mice began many years ago, when Fuchs and her team began searching for factors that determine how embryonic skin cells are able to choose between becoming epidermis or a hair follicle. "Hair is so structurally different from the epidermis that it seems extraordinary that you can generate both structures from one cell type," Fuchs says. "So we asked two questions: How does this happen, and what signals dictate this decision?"
For clues, Fuchs began looking at fibrous proteins called keratins. "We noticed that a potential regulatory sequence in a group of hair keratin genes was identical to a sequence that exists in lymphoid genes that are regulated by lymphoid enhancer factor (Lef-1)," Fuchs said. Lef-1 is what molecular biologists call a transcription factor, a protein that can combine with other proteins and then bind to specific sites on DNA, turning genes either on or off. They found that in adult mice, Lef-1 is expressed in the transiently dividing precursor cells of the follicle that go on to express the hair keratin genes. Surprisingly, Lef-1 was also expressed in embryonic skin. The pattern of Lef-1 had a certain "paint-by-numbers" quality, appearing on the surface of an embryo in a specific dot pattern that corresponded to where hair follicles are going to appear on the surface of the adult skin. "That began to lead us to wonder if Lef-1 might be important for the decision-making process that instructs embryonic skin to form a hair follicle," Fuchs says.
Around this time, Rudolf Grosschedl and colleagues at the University of California, San Francisco, found that when they knocked out the gene that codes for Lef-1 in mice, the animals had far fewer hair follicles than normal. And not long after that discovery, many laboratories simultaneously reported that Lef-1 has a partner in its function as a transcription factor: ß-catenin. "That work led us to wonder if ß-catenin may not also be playing a central role in the development of the hair follicle," says Fuchs.
ß-catenin is an interesting protein that has two very different functions in the body, Fuchs points out. Its most studied role is to bind neighboring cells together to facilitate communication between them, a process known as cell-cell adhesion. Any excess ß-catenin made during this process is quickly marked for degradation.
Several years ago, researchers also discovered that ß-catenin was a key player in what is known as the "Wnt signaling pathway," a major biochemical route that determines the developmental fate of cells. For embryonic skin cells, that fate is to become either an epidermal cell or a hair follicle cell. The Wnt pathway may help decide that fate through its ability to transiently inhibit the breakdown of ß-catenin. When the Wnt pathway is active, normal ß-catenin degradation stops. As a result, leftover ß-catenin can accumulate within cells. If those cells contain Lef-1, ß-catenin will not interact with it to create an active transcription factor.
