TERT Grows Hairy Mice at Stanford University

Kavita Y. Sarin [1,3], Peggie Cheung [1], Daniel Gilison [1,3], Eunice Lee [1], Ruth I. Tennen [1,2], Estee Wang [1], Maja K. Artandi [1], Anthony E. Oro [2,4], and Steven E. Artandi [1,2],

“Conditional Telomerase Induction Causes Proliferation of Hair Follicle Stem Cells,”

Nature, Vol. 436, pp.1048-52 (August 18, 2005).

1. Department of Medicine

Division of Hematology

2. Cancer Biology Program

3. Department of Genetics  

4. Department of Dermatology

Stanford School of Medicine

Stanford, CA 94305; USA

Correspondence to: Steven E. Artandi [1,2]

Correspondence and requests for materials should be addressed to S.E.A.

(E-mail: sartandi@stanford.edu).

Received: February 13, 2005; Accepted: May 6, 2005.

Abstract:

              TERT, the protein component of telomerase[1, 2], serves to maintain telomere function through the de novo addition of telomere repeats to chromosome ends, and is reactivated in 90 percent of human cancers. In normal tissues, TERT is expressed in stem cells and in progenitor cells [3], but its role in these compartments is not fully understood. Here we show that conditional transgenic induction of TERT in mouse skin epithelium causes a rapid transition from telogen (the resting phase of the hair follicle cycle) to anagen (the active phase), thereby facilitating robust hair growth. TERT overexpression promotes this developmental transition by causing proliferation of quiescent, multi-potent stem cells in the hair follicle bulge region.

              This new function for TERT does not require the telomerase RNA component, which encodes the template for telomere addition, and therefore operates through a mechanism independent of its activity in synthesizing telomere repeats. These data indicate that, in addition to its established role in extending telomeres, TERT can promote proliferation of resting stem cells through a non-canonical pathway.

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News and Views: Cell Biology:

“Shaggy Mouse Tales: Stem Cell/Telomere Link”

by

Elizabeth H. Blackburn, Nature, Vol. 436 (August 18, 2005). 

              Regenerating tissues such as skin and blood require high rates of cell turnover, which occurs through the tightly regulated division of tissue stem cells. The genes and proteins that control stem-cell behavior remain largely unknown, but now a critical connection between stem-cell function and the protein component of telomerase, TERT, has been discovered. Conditional activation of TERT in skin epithelium activates resting hair-follicle stem cells, resulting in rapid hair growth. This is distinct from TERT's role in extending telomeres, the caps that protect the ends of chromosomes, and suggests new ways of treating disorders associated with tissue injury and aging. First impressions can be misleading. The enzyme telomerase has been well studied because of its initial association with cell aging processes and cancer -- but it now seems that this is not all it can do...

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“Furrier Mice Yield Stem-Cell Discovery”

by

Nicholas Wade, Senior Science Editor, The New York Times

August 18, 2005; By making mice grow furrier coats, researchers have discovered that an enzyme known to serve as a last-ditch defense against cancer also activates adult stem cells, which the body uses to repair its tissues. The insight could lead to new treatments for certain diseases, possibly even promoting hair growth in animals other than mice.

              The research, reported by Steven E. Artandi and colleagues at Stanford University in Nature today, shows that adult stem cells can be activated by an enzyme called telomerase. The finding is surprising because telomerase is well known in a quite different context, protecting against tumors by limiting the number of times a cell can divide. The new findings put the enzyme astride two major biological pathways, one that promotes the growth of new cells for maintaining tissues and the other that prevents the excessive growth that leads to tumors.

              The finding is "very interesting and very tantalizing," said Prof. Carol Greider, a telomerase expert at the Johns Hopkins University, who was not involved in the research. Dr. Artandi chose to study the effects of telomerase on mouse fur not to develop a Rogaine for rodents, but because mice have an easily accessible stem-cell system built into their skin. Each hair follicle has attached to it a small bulb full of stem cells. When the stem cells are activated, the follicle grows a new hair shaft.

              Dr. Artandi's team genetically engineered a strain of mice in which the telomerase gene could be turned on with a drug. When the mice were given this drug, the stem cells in their hair follicles proliferated, and the mice grew extra furry coats.

              The usual role of telomerase is to maintain the telomeres, special lengths of DNA that cap each end of the chromosomes. But it performs this service only for egg and sperm cells and to some extent for stem cells. The telomerase gene is switched off almost entirely in normal cells. So each time a normal cell divides, its telomeres become shorter, and after they dwindle to a certain length, the cell is forced into senescence and cannot divide again. For several years, there have been hints that the telomerase protein performs some role other than just maintaining telomeres. Dr. Artandi said he had decided to look for that role in stem cells, because the gene that makes the enzyme is active in these cells.

             To avoid confusion with the telomere-lengthening role of telomerase, he engineered the mice to lack the additional biochemical machinery needed to maintain telomeres. Thus, when the mice were fed the telomerase-activating drug, the telomerase must have activated the stem cells in some way that did not involve their telomeres.

              Dr. Artandi said he did not yet know how telomerase activated stem cells. But when this new pathway is understood, it may suggest ways of tackling diseases in which the right cells fail to proliferate like pancreatic islet cells in diabetes.

              Normal male mice do not go bald as they age, but the research could still be significant for human beings. Anthony Oro, a Dermatologist and co-author of the report, said the great challenge in male-pattern baldness was how to restart the arrested follicles. The finding about telomerase in mice "doesn't prove that this is the master regulator of all hair follicle cycling," Dr. Oro said, but it helped define the players.

              Telomerase experts not involved in this study are enthusiastic about the finding, which opens out an unexpected line of inquiry about their favorite gene. "I think it is an extremely important observation," said Prof. Ronald DePinho of the Harvard Medical School. Prof. Elizabeth Blackburn of the University of California, San Francisco, said that "biologically it's intriguing" that telomerase should have two such different roles. But, Dr. Blackburn added, it is too early to know whether this is just one of nature's frequent economies in using the same protein to do two things.

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STANFORD: “Shaggy-Haired Mice Aid Cell-Aging Research:

Unexpected Results Hint at New Ways of Looking at Stem Cells”

by

Carl T. Hall, Science Writer, San Francisco Chronicle, pp. B1,7

August 18, 2005; Stanford University biologists have created a strain of long-haired laboratory mice that suggest a surprising new role for an enzyme already linked to aging and cancer. Steven Artandi, a Stanford cancer biologist, graduate student Kavita Sarin and colleagues reported today that a key component of the enzyme, known as telomerase, can switch on stem cells resting in mouse hair follicles. The otherwise ordinary-looking mice promptly became as shaggy as '70s rock stars -- a wholly unexpected result that hints at new ways of understanding stem cell biology and age-related disorders.

              It's unlikely to produce a baldness cure anytime soon, however. The mice had to be genetically engineered from birth to carry the special hair-growth machinery, Artandi noted during an interview. "This doesn't present an immediate drug to treat male-pattern baldness, definitely not," he said.

              The experiments, reported in today's issue of the journal Nature, further burnish the Bay Area's status as a leading center of cellular-aging research. Some of the main functions of the telomerase enzyme have been unraveled by scientists at UCSF, led by microbiologist Elizabeth Blackburn. Earlier work by Blackburn and others showed how telomerase can forestall the molecular machinery of aging by rebuilding protective DNA structures known as telomeres, found at the tips of chromosomes.

              As most normal cells divide, these tips wear down, eventually signaling the cells it's time to die. Telomerase rewinds this molecular clock by rebuilding the tips, bestowing biological immortality on the cell. One of the hallmarks of fast-growing cancer cells is a ready supply of telomerase. Blackburn wrote a commentary on the new research in the same science journal, suggesting there may be other roles for telomerase waiting to be discovered. She also dug into the history books to address the possibility of telomeric hair tonics someday being touted on late-night TV. "In ancient Egypt, men smeared their pates with hippopotamus fat in a desperate bid to stave off baldness," she said. "Is telomerase the new hippopotamus fat? Probably not. But this enzyme is already known to be vital in sustaining tissues in health and disease, and we should look beyond its eponymous function to understand the full spectrum of its potential roles."

             The new research documents how one component of telomerase -- known as Telomerase Reverse Transcriptase (or TERT for short) -- affects stem cells in the skin, a function that appears to be independent of the enzyme's other roles in cancer and aging. Stem cells, found in virtually all organs of the body, are the wellsprings of tissue regeneration. Specialized stem cells in the hair follicles cycle between a quiescent and active state. The timing of these cycles helps to regulate hair growth. In the mouse studies, researchers found that the TERT molecule "can kick these resting stem cells into action," Artandi said.

E-mail: Carl Hall at chall@sfchronicle.com.

URL: San Francisco Chronicle.