Science Editor

The Wnt/beta-catenin pathway is a master regulatory pathway in embryonic development, and hotly pursued by pharmaceutical companies because it is deregulated in several cancers.

In the April 15, 2010, edition of Nature, researchers described how loss of one Wnt inhibitor can lead to another, milder problem as well: hair loss in a genetic disorder, hereditary hypotrichosis simplex, that shares certain features with male pattern baldness and other hair loss disorders.

As problems with the Wnt pathway go, hair loss is of course preferable to cancer. But that does not mean that it is a mere vanity disorder. As the National Alopecia Areata Foundation wrote on its web site, that disease - an autoimmune disease that is characterized by the loss of hair in round patches and usually beginning in childhood - is "not life-threatening, [but] most certainly life-altering, and its sudden onset, recurrent episodes and unpredictable course have a profound psychological impact on the lives of those disrupted by this disease."

The findings now published in Nature do not, by themselves, either explain more common forms of hair loss such as male pattern baldness or immediately suggest a treatment. But senior author Angela Christiano, who is a professor of dermatology and genetics and development at Columbia University Medical Center, said in a press release that "We have at last made a connection between Wnt signaling and human hair disease that is highly significant. . . . We have years of beautiful data in our field about hair growth in mice, but this is the first inroad into showing that the same pathway is critical in human hair growth. This is the first mutation in a Wnt inhibitor that deregulates the pathway in a human hair disease."

Christiano and her colleagues found the new inhibitor through genetic analysis of two families that suffer from hereditary hypotrichosis simplex. In this disease, follicles atrophy beginning in childhood, and become unable to support regular hair, which is replaced by "vellus hair," otherwise known as peach fuzz. Hair follicle degeneration also underlies other forms of hair loss, such as androgenetic alopecia, alopecia areata and male pattern baldness.

Christiano and her colleagues first conducted genetic analysis in two families with hereditary hypotrichosis simplex, which is an autosomal dominant disorder, and found a missense mutation in a particular gene on chromosome 18: adenomatosis polyposis down-regulated 1, or APCDD1.

Cell culture experiments, as well as experiments in developing chicks and frogs, suggested that APCDD1 is a membrane-bound protein that interacts with wnt3a and LRP5, two proteins that are part of the Wnt pathway. The Wnt pathway affects hair growth in mice, but the new study is the first work to directly implicate it in human hair growth.

Developing therapies could, however, be complicated by the fact that adenomatosis polyposis down-regulated 1 - as its name might suggest - also has a relationship to colon cancer. The 2002 paper first describing the protein noted in its title that it has "probable involvement in colorectal carcinogenesis," though no follow-up studies appear to exist. (Less worrisome, the gene also has a role in shell development for turtles.)

Nevertheless, Christiano said that "These findings suggest that manipulating the Wnt pathway may have an effect on hair follicle growth - for the first time, in humans. . . . And unlike commonly available treatments for hair loss that involve blocking hormonal pathways, treatments involving the Wnt pathway would be nonhormonal, which may enable many more people suffering from hair loss to receive such therapies."