Development of hair depends on development of the hair channel

There's more to a building than the materials that comprise it; equally important is the foundation that underlies and supports the main structure. Similarly, researchers at The Rockefeller University and the Howard Hughes Medical Institute led by Elaine Fuchs, Ph.D., now show that hair inherently depends on the channels in skin that hold it.
Working with mice as a model organism, the scientists initially pinpointed a protein called GATA-3 as a possible trigger of hair channel development. Based on its location within the hair and the timing of its appearance, GATA-3 stood out as a strong candidate for instructing skin stem cells to transform into hair channels instead of hair. Analyzing mice previously engineered to lack this protein not only confirmed this suspicion, but led to the discovery of a genetic connection between the hair channel and hair: without GATA-3, the mice grew an unusually short and stubby coat.

"This study illustrates for the first time the interrelationship between hair and the hair channel on a genetic level," says first author Charles Kaufman, an M.D.-Ph.D. student at the University of Chicago who studied in the Fuchs lab at Rockefeller.

"Simply put, you can't have a proper hair without a channel."

The findings, reported in the Sept. 1 issue of Genes & Development, provide researchers with a clue about how to culture living hair in the laboratory.

"For 20 years, scientists have been able to grow hairless skin in a Petri dish from a sample of skin stem cells, and this technology has been useful clinically in the treatment of burns and wounds. However, cultivating hair has proven to be a far greater challenge," says Fuchs, professor and head of the Laboratory of Mammalian Cell Biology and Development at Rockefeller and a Howard Hughes Medical Institute investigator.

"Part of the reason for this may be that researchers simply haven't appreciated the importance of the hair channel in forming the hair."

Like grafting skin for wounds, researchers might eventually be able to transplant hair for the treatment of balding. The latest results bring scientists one significant step closer to this goal, in addition to the opposite possibility of removing unwanted hair in a condition known as hirsutism.

What is more, the new research comes with a surprising twist.

In the mid 1990s, at the University of Chicago, Fuchs and colleagues hit upon the startling discovery that a protein that promotes the formation of immune cells, called T cells, also triggers stem cells to become hair rather than skin. Called Lef1, this protein is a component of the Wnt signaling pathway. In their recent study at Rockefeller University, the Fuchs lab noted a similar relationship between the hair channel and T cells: GATA-3, the protein identified as a novel promoter of hair channel development, has been previously shown to play an essential role in determining T-cell fate.

"It seems that the body may have chosen to recycle the same proteins in the development of different tissues," says Kaufman.

Adds Fuchs, "Knowing this uncovers an intriguing parallel between the pathways taken by the stem cells of our immune system and those of our skin. This knowledge may help us to understand more about the fundamental properties of stem cells in the body."

Yin and yang of hair follicles

The hair follicle consists of the hair shaft -- what we shampoo and comb daily -- and, embedded within the skin, a rigid channel that holds the hair shaft called the Inner Root Sheath (IRS). Scientists believe that the main purpose of this channel is to shape and guide a developing hair; its outer, tough cells are thought to mesh like gears with the hair shaft to produce the familiar shingled look of hair as seen in commercials about hair care products.

At the base of the hair follicle lies a storehouse of replacement cells, called matrix cells, capable of transforming into hair channel or shaft cells. Also within the hair follicle lies an even more versatile reservoir of cells -- skin stem cells. These cells have the potential to become skin or hair.

Fuchs and her colleagues have contributed much to our understanding of hair shaft development. In addition to identifying Lef1 as a hair precursor protein in the mid 1990s, the researchers found last March that the inhibition of an extracellular signaling protein called BMP also is required. Together, these findings indicate that before a hair can be produced, both a Wnt signal and a Bmp inhibitory signal must be received by the precursor cell.

However, when it came to the hair channel, little was known.

Who's the boss?

To hunt down the genes in control of channel development, the Rockefeller researchers narrowed their search to a type of gene or protein called a transcription factor. Transcription factors are like the bosses in the hierarchy of a cell's proteins: they order other worker proteins to carry out specific tasks, including the recruitment of more proteins to the job at hand. Reasoning that a transcription factor heads the job of transforming primitive cells into mature hair channel cells, the researchers looked for only those transcription factors that became activated at the same time that channel cells arose in developing embryos.

Identifying GATA-3 as one such commander-in-chief, the scientists then set out to characterize its role in the cell.

"That GATA-3 could be a regulator of hair or hair channel development fit with the previous observation that hair cells and T cells share some developmental regulators," says Kaufman.

Shaft or sheath?

To determine the role of GATA-3, the scientists examined mice that lacked the gene that codes for this protein. Because these "knockout" mice typically die early in life, the researchers grafted their skin onto other adult mice for further study. This experiment allowed them to observe how the absence of GATA-3 affects skin after the birth of the mice. What they observed was a malfunctioning set of channels: the three cell layers which form the channel were nearly completely absent.

But in addition to the channel defects, the hair shaft of the grafted skin was affected: hairs grew abnormally short and thick. According to the researchers, these hair shaft irregularities were caused by both faulty hair channels as well as internal disruptions.

"We found that some of the genes in the hair shaft were misexpressed, which implies a certain level of 'cross-talk' between the shaft and channel," says Kaufman.

"This means that when the two cell types are forming, there is some communication that takes place between them, probably to ensure proper growth."

Now that the researchers have unmasked an important transcription factor controlling the fate of the hair channel, their next step is to identify the ultimate mastermind -- the extracellular signaling protein required for the activation of GATA-3. Says Fuchs, "Knowing what externally promotes hair channel lineage would round out our knowledge of the hair follicle as a whole."


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Other authors of this paper are: H. Amalia Pasolli and Michael Rendl at The Rockefeller University; Diana Bolotin, a University of Chicago M.D.-Ph.D. student working at Rockefeller University; Kim-Chew Lim at University of Michigan; Xing Dai at University of California, Irvine; and Ping Zhou and Maria-Luis Alegre at The University of Chicago.

This research was funded by the National Institutes of Health and Howard Hughes Medical Institute.