Some of us are hairier than others. And some regions of our otherwise nude skin - from head to underarms to pubis - are hairier than others. It takes a sizeable symphony of cells, genes, proteins, tissues and other molecules to decide where and when a developing mammalian fetus will deposit future skin and hair.

In a developing mouse embryo, a sheet of tightly adhering epithelial stem cells form on the body surface. Beginning at the 13th gestational day following fertilization, some of these stem cells receive growth signals that tell them to cut loose from neighboring stem cells. Their next embryonic assignment is to move downward and form a pocket that will become a hair follicle. Surrounding cells that don't receive these messages continue to develop into the skin cells that will form the epidermis - the body's waterproof outer coat. While this skin or hair drama proceeds, other stem cells are migrating away from that sheet of cells to fashion teeth, lungs and other organs.

"Stem cells that create epidermis or hair," observed cell biologist Elaine Fuchs, "have become a model system to study, because they are plentiful in adult skin, and can continually propagate in a laboratory Petri dish. So researchers can study the genes and proteins involved in turning stem cells into epidermis or hair follicles.

"The skin epidermis is a multilayered tissue," she explained. "At its innermost layer, epithelial stem cells give rise to progeny that divide several times before they are pushed upward and differentiate to produce the body's skin barrier that keeps harmful microbes out and fluids in. The cells that reach the skin surface are dead and sloughed off, continually replaced by inner-layer cells moving outward. Every two weeks," Fuchs noted, "the epidermis is nearly brand new."

Fuchs is a professor on the faculty of The Rockefeller University in New York. She is senior author of a paper in Nature dated March 20, 2003. It's title: "Links between signal transduction, transcription and adhesion in epithelial bud development."

"The findings of this study," Fuchs observed, "identify the external signals that are naturally present in developing skin and that stimulate the production of hair follicles. On a basic science level," she added, "it provides further support to the idea that cell parts known as adherens junctions - once thought useful only as the glue that holds cells of a tissue together - actually play an important role in controlling when certain genes are turned on or off, thus transforming the essential nature of the cell."

Beta-Catenin + Lef-1 Play In Harmony

Fuchs and her team previously discovered that a protein called beta-catenin is a key player in formation of hair. Accumulation of this protein in certain cells may be a critical early step in selecting the developmental pathway of several stem cells in the body. Beta-catenin works in concert with a transcription factor known as Lef-1 - lymphoid enhancer factor. The Fuchs lab found that in mice, Lef-1 is expressed in stem cells that become hair follicles but not in those destined for skin epidermis.

The scientists suspected that beta-catenin and Lef-1 together produced changes in the stem cell that pushed it to morph into hair - but they didn't know how at that time. Proof of their findings came when they altered genes in experimental mice to overproduce both proteins. Skin cells on those mice grew luxuriant hair.

"However," Fuchs said, "these same genetic changes formed benign tumors around the new hair follicles because the beta-catenin continually pushed new stem cells to form hair. Such genetic manipulation," she commented, "is obviously not an answer to human hair woes.

"Before stem cells differentiate," Fuchs explained, "they are locked together in tight sheets, zipped to one another. The protein that formed the teeth' of these zippers is known as E-cadherin. They are called adhesion' proteins because they stick to each other like Velcro. They help maintain the shape of the cell and its links to its neighboring cells. These stem cells become skin."

Two Proteins - Wnt, Noggin - Roll Stem Cell Dice

Fuchs then went on to clarify what happens when that same cell receives growth signals to change shape and become a hair follicle. In a series of knockout [KO] mice she and her co-authors found that two critical growth factors, Wnt and noggin by name, were needed as simultaneous inputs to the embryonic stem cell.

"First," she said, "noggin signals the cells to make the Lef-1 transcription factor. Then the Wnt protein prompts a cascade of signals to turn off the machinery that degrades excess beta-catenin, which binds to Lef-1.

"Because the Wnt and noggin proteins occur naturally in humans," Fuchs observed, "our research proved to be clinically relevant. The Wnt pathway involved in hair growth," she pointed out, "has already been implicated in the spread of some malignancies, such as breast and colon cancer."

Using KO mice genetically altered not to produce noggin, the researchers showed that the Lef-1 transcription factor was not being expressed. Experiments in which the level of E-cadherin was kept high blocked output of hair follicles, because E-cadherin production must be reduced in order for stem cells to loosen and reorganize to form follicles.

The Nature article's first author, Colin Jamora, noted: "Our finding that the beta catenin/Lef-1 transcription complex turns down the expression of the gene that encodes E-cadherin is completely novel, since this complex was known only to turn genes on."

"The description of how Wnt and noggin produce structural changes in a stem cell may ultimately shed light on several developmental and disease processes," Fuchs pointed out. "Mutations in E-cadherin and problems in the Wnt-signaling pathway have already been linked to some cancers," she noted. "The reason why tumor cells can't interact properly with other cells may be that their levels of adherent junction proteins are not maintained. For example, squamous cell skin cancers are large masses of cells that invaginate downward. Too much or too little E-cadherin," she mused, "is a bad thing. With too much, hair can't develop. With too little, cancer can result.

"Our research may also prove relevant," Fuchs concluded, "to a much less serious but more common condition - baldness."