MOLECULAR CONTROLS ON HAIR PRODUCTION
Recent studies suggest that Wnt proteins play a major role inducing embryonic skin cells to make hair follicles and, later, in prodding follicle cells to make hair throughout life. Wnts instruct cells to stop breaking down another protein, beta-catenin (B-CAT), which joins with LEF1 or a related protein to help activate specific genes. Those genes, in turn, give rise to proteins that cause the cells to specialize and contribute to follicle or hair formation. Molecules in, or interacting with, the Wnt signaling pathway could on day serve as targets for drugs aimed at enhancing or diminishing hair production.

PROTEINS THAT MAY INTERACT WITH THE Wnt SIGNALING PATHWAY IN THE SKIN

Born to Cycle
FOLLICLES BEGIN CYCLING within two or three years after birth. The cycle has been shown to have three main stages. In catagen, the epithelial cells below the bulge essentially commit suicide, leaving behind the dermal papilla and a membrane (the basement membrane) that formerly encased the now dying region. As the cells die, this membrane contracts and draws the dermal papilla up to the bulge. (In the scalp, this trip takes about two weeks.) Meanwhile the hair shaft loses its anchor deep in the dermis. It therefore becomes prone to shedding in the next two stages.
When the dermal papilla reaches the bulge, follicles enters telogen, the resting phase. Telogen can last about three months in the human scalp, but its duration can be modulated by a range of factors. Plucking hair wounding the follicles can shorten it, for instance.
Anagen follows telogen. Early on some of the stem cells from the bulge divide and travel down along the basement membrane and become matrix or outer toot sheath cells. Once formed, the matrix cells proliferate and ultimately give rise to the hair cells and the inner root sheath, repeating the steps that occur during embryonic development. This repetition implies that the events of an anagen are probably controlled by a number of the same signaling molecules that operate during development.
The reconstituted anagen follicles produce an inch of hair every tow months or so in the scalp and usually keep this up for six to eight years. The length of anagen determines how long a single hair can grow. On any given day in the life of a typical 20-year-old, about 90 percent of the scalp follicles are in the productive, hair-growing phase, and about 10 percent are decaying or inactive; approximately 50 to 100 hairs are shed.
Hair thinning generally happens not because follicles disappear but because the ratio of follicles in the growing and no-growing phases shifts unfavorably. Also, many follicles in balding people shrink progressively, ultimately producing only small, colorless hairs.
As is true during follicle development in the embryo, during anagen signals from the dermal papilla instruct the matrix cells to divide and subsequently differentiate into hair cells. For this reason, scientists have become very interested in uncovering the nature of the signals issued by the dermal papilla during development and cycling. They don’t have the answer yet, but in the past few years Elaine Fuchs and her colleagues at the University of Chicago have discovered that the dermal papilla's signals probably convey their directives largely by activating still other signaling molecules-members of the Wnt family of proteins. Wnt proteins have long been recognized as key regulators of varied developmental processes in mammals and other organisms.

The Hand on the Helm
FUCHS STUMBLED ACROSS the first clues to the importance of Wnts to hair about six years ago. At the time, for reasons unrelated to treating human hair disorders, she wanted to identify the signaling molecules that instruct certain matrix cells to begin producing hair keratins.
Often a cell will initiate a behavior, such as making new proteins, after a molecule from the outside binds to a receptor on the cell surface and triggers a cascade of molecule interactions on the inside. These signaling cascades frequently lead to the activation of specific genes in the nucleus, culminating in the production of the proteins and genes encode. Knowing this, Fuchs began her search for the molecules that dictate the conversion of matrix cells to hair cells by trying to identify the molecules in the nucleus that switch on the hair keratin genes.
In 1995 her group discovered that a regulatory protein called lymphocyte enhancer factor 1(LEF1) participated in activating the hair keratin genes. It was also present during hair follicle formation in the embryo, where it appeared in the earliest clusters of ectoderm cells as well as in the cells destined to form the dermal papilla. Presumably on orders form some outside signal, LEF1 became active and helped to turn on genes needed for follicle formation or hair growth. Consistent with this conclusion, Rudy Grosschedl and his co-workers, then as the University of California at San Francisco, discovered that without LEF1, mice fail to make a furry coat. And when Fuchs's team engineered mice that produced excess LEF1 in the skin, the animals produced more hair follicles than normal.
At the same time, other groups demonstrated that LEF1 cannot activate genes on its own; rather it must first couple with a second protein, beta-catenin normally helps to form junctions with neighboring cells. In the absence of Wnt signaling, an enzyme inside the cells marks any unused beta-catenin for destruction. Wnts instruct cells to handcuff that enzyme. With the enzyme out of commission, beta-catenin becomes free to accumulate and to pair with LEF1 or one of its relatives.
Combined with Fuch's discoveries, these results suggested that Wnts and rescued beta-catenin molecules might be central in both follicle formation and hair production. Subsequent studies in mice added support to that nation. For instance, Fuchs's group devised a way to flag cells that activated LEF1 binding genes in response to a Wnt signal in a developing embryo. Those experiments implied that Wnt is the mesoderm-issued signal that instructs the overlying ectoderm to begin forming an appendage and is likewise the ectodermal signal that tells the underlying mesoderm to form the dermal papilla. What is more, much later in development, after follicles have formed, Wnt appears to be the message that directs matrix cells above the dermal papilla to differentiate into hair cells.
Even more dramatic evidence for the central importance of Wnts came when Fuchs' s group created mice that, after birth, could not degrade beta-catenin in their epidermal cells, a feature that made the cells behave as if they were endlessly receiving a Wnt signal. As adults, these rodents acquired an unusually lush coat by forming new hair follicles between the hones that were laid down during embryonic development.
The production of new follicles is certainly exciting, but a couple of other findings form the mouse studies might make balding readers think twice before tracking down Fuchs and begging her for vials of Wnt to pour on their heads. As the furry rodents aged, they acquired benign lumps that resembled a common human scalp tumor called pilomatricoma. Fuchs's laboratory subsequently demonstrated that in humans these tumors arise when a mutation in the beta-catenin gene prevents the protein's breakdown. Wnts and extra beta-catenin have also been implicated in cancers of the colon, liver, breast and reproductive tract.
To Fuchs, all these results, including the unfortunate mouse tumors, provide useful information for scientists interested in treating hair disorders. They teach that Wnts are major regulators of follicle developments and cycling but simply delivering Wnts by constant application would not be feasible as a human therapy, because of the tumor risk. The trick to correcting hair maladies, Fuchs contends, may be to deliver Wnts in a patterns that mimics nature better or to manipulate other steps in the Wnt signaling cascade.
To do that, scientists need still more information about the Wnt signaling pathway and about other factors in the skin that influence it. Which Wnts, and which of their numerous receptors, are involved at different steps of the hair cycle and in follicle development, and what molecules control their production? And which molecules inside Wnt target cells determine how these cells respond to Wnts, such as whether they become hair cells or other parts of a follicle?
Research into signaling pathways that interact with the Wnt pathway will surely offer some clues to the answers. Scientists who study many different tissues and organisms have identified a host of proteins in such pathways, including sonic hedgehog, transforming growth factor-beta, bone morphogenic protein, noggin and fibroblast growth factor, to name just a few.
Sonic hedgehop could be particularly crucial for hair growth. Like Wnt proteins, it carries a signal form one cell to another and is known to participate in the proper development of embryos. Further, sonic-hedgehog and Wnt-signaling pathways often influence each other. Investigations reveal that although sonic hedgehog is not needed for formation of the hair germ, it is needed for subsequent conversion of the germ to a full-fledged follicle. And last year Ronald G. Crystal of Weill Medical College of Cornell University found that when hair follicles in adult mice are induced to make the protein during the resting, telogen stage, the follicles shift prematurely into the hair producing, anagen stage. Thus, sonic hedgehog can stimulate dormant follicles to begin producing hair.
Although treatment with sonic hedgehog might seem an attractive idea for inducing hair growth, too much signaling by this molecule results in basal-cell skin cancers in humans. To develop therapies that involved sonic hedgehog, Wnts or other proteins able to induce cell division, pharmaceutical manufactures would fist have to make sure that those molecules were properly controlled.
The effects of bone morphogenic proteins and different forms of transforming growth factor-beta on Wnt signaling are proving difficult to sort out. But some scientists suspect that when that task is done, those proteins, too could prove useful for stopping or starting hair growth.

Styling Therapy
IDENTIFYING THE MULTITUDE of molecules that coordinate the development and cycling of hair follicles is clearly a daunting job. Yet thanks to the rapid pace of technological advancement, researchers should soon be able to discern all the genes that are activated in purified populations of cells at different stages of follicle development and cycling. With this information at the ready, they could assess how these complex patterns of gene activity are altered in people who have hair disorders. The technology should also enable skin biologists to uncover new proteins important to hair production as well as to specify which ones contribute to different disorders.
As researchers become more sophisticated in their knowledge of the molecular interactions underlying hair growth, they can begin animal testing of compounds that might restore order to deranged regulatory pathways and revive dormant follicles. If those tests go well, human scalp skin can be transplanted onto mice incapable of rejecting it to determine whether human and mouse follicles respond comparably to the agents. And if those results are good, investigators may attempt human trials of the most promising drug candidates.
No one can predict how soon dermatologists and pharmaceutical companies will be able to produce new therapies built on the discoveries emerging form basic research into hair follicle developments and cycling. But research is progressing remarkably fast. If the pace continues, Fuchs predicts, much of the information that is needed to understand the complex controls on hair manufacture will probably be in hand within the next five years.

Ricki L. Rusting is a staff editor and writer.

MORE TO EXPLORE
The Secret Life of the Hair Follicle. Margaret H. Hardy in Trends in Genetics, vol. 8, No.2, Pages 55-61; February 1992.
The Biology of Hair Follicles, Ralf Paus and George Consarelis in New England Journal of Medicine, Vol. 341, No.7, Pages 491-497; august 12, 1999.
Multiple Roles for Activated LEF/TCF Transcription Complexes During Hair Follicle Development and Differentiation, Ramanuj Das Gupta and Elaine Fuchs in Development, Vol. 126, No. 20, pages4557-4568; October 1, 1999.
Stem Cells: A New Lease on Life, Elaine Fuchs and Julia A. Segre in Cell, Vol. 100, No.1, pages143-155; January 7, 2000.
Involvement of Follicular Stem Cells in Forming Not Only the Follicle but Also the Epidermis, G.Taylor, M.S. Lehrer, T.T. Sun and R.M. Lavker in Cell, Col. 102, No. 4, pages 451-461; August 18, 2000.
Morphogenesis and Renewal of Hair Follicles from Adult Multipotent Stem Cells, H. Oshima, A. Rochat, C. Kedzia, K. Kobayashi and Y. Barrandon in Cell, Vol. 104, No. 2, pages 233-245; January 26, 2001
General information about hair can be found at www.keratin.com

Overview /Hair Growth
Biologists now understand many of the steps leading to the development of hair follicles in embryos and of hair production throughout life.

Signaling proteins in a family known as Wnt play a role in directing many of those steps. Researchers are uncovering additional regulatory molecules as well.

Baldness often arises not because follicles die but because they shrink and malfunction. Drugs that manipulate Wnts or other regulatory proteins might one day protect threatened follicles and prod shrunken ones into producing hair normally again.

Knowledge of the controls on hair production could also lead to new ways of eliminating unwanted hair.

MOLECULAR CONTROLS ON HAIR PRODUCTION
Recent studies suggest that Wnt proteins play a major role inducing embryonic skin cells to make hair follicles and, later, in prodding follicle cells to make hair throughout life. Wnts instruct cells to stop breaking down another protein, beta-catenin (B-CAT), which joins with LEF1 or a related protein to help activate specific genes. Those genes, in turn, give rise to proteins that cause the cells to specialize and contribute to follicle or hair formation. Molecules in, or interacting with, the Wnt signaling pathway could on day serve as targets for drugs aimed at enhancing or diminishing hair production.