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RESEARCH BRIEFS
Discovery Rewrites Text on Tendon DevelopmentFor centuries, students of developmental biology learned that the somites--segments of the early vertebrate embryo that give rise to the skeletal muscle, skeleton of the trunk, and dermis--had three compartments: myotome, sclerotome, and dermomyotome.
A six-day-old chicken embryo is labeled by in situ hybridization to highlight expression of the Scleraxis gene. Ava Brent and colleagues showed that this gene directs development of the axial tendons in vertebrates. (Image courtesy of Ava Brent) Now, thanks to the molecular detective work of HMS researchers, future textbooks may be revised to add a fourth compartment, the syndetome, which gives rise to the tendons that connect bone and muscle. Its name, coined by the scientists, derives from the Greek syndesis, to bind together. Ava Brent, a fourth-year graduate student in the laboratory of Cliff Tabin, discovered the new compartment, which had eluded scientists until now because its cells are not visibly distinct from those of the adjacent bone-forming sclerotome. No one knew where in the trunk of the early embryo the tendons arose. Working with Tabin, professor of genetics at HMS, and Ronen Schweitzer of Oregon Health Sciences University, Brent took advantage of the recent discovery that the transcriptional regulatory gene Scleraxis (Scx) is expressed uniquely and continuously in developing and mature tendons. First, they used in situ hybridization to confirm Scx expression in tendons of 10-day chick embryos. Then they looked at earlier chick embryos, at the stage when somites are developing, and found Scx expression in cells lying between the cell populations that grow into muscle and those that form bone--prefiguring the anatomical location of mature tendons. Next, they created chimeric chick-quail embryos in which quail cells could be detected with an antibody. This allowed them to show that the syndetome emerges from the sclerotome. In addition to mapping the origin of tendons, Tabin said, they described the "crosstalk between cell populations" directing the formation of the syndetome, which involves a fibroblast growth factor signaling pathway. "The future muscle tells cells that otherwise would become skeleton to become tendon instead," he said. "This places the forming tendon tissue in the correct relative position. It's a nice paradigm for how tissues can be established in a way that forces them into the right relative organization during embryogenesis." The study is published in the April 18 Cell. --Tom Reynolds
P53 Relative May Confer Sensitivity to Cancer DrugsP53 plays a key role in controlling cancer as well as in the response of cancer to therapy. It accumulates in cells after the administration of chemotherapy drugs and initiates programmed cell death. But only about half of human cancers contain functional p53, so determining why some tumors that lack the functional protein nevertheless respond to chemotherapy has been a challenge. Now HMS scientists report in the April Cancer Cell that a p53 family member, p73, may be responsible for making cancer cells sensitive to chemotherapy. "It was known p73 was rarely mutated in cancer and levels tended to be higher in cancer cells compared to normal cells. It was also known that mutant forms of p53 can inactivate p73. Furthermore, it was known that certain forms of mutant p53 could block killing by chemotherapeutic agents," said senior author William Kaelin, a Howard Hughes investigator and HMS professor of medicine at the Dana-Farber Cancer Institute and Brigham and Women's Hospital. In their experiments, Kaelin, lead author Meredith Irwin of DFCI, and their colleagues found that p73 is, indeed, induced in cancer cell lines treated with chemotherapeutic agents. Further experiments showed that blocking p73 led to increased resistance of cancer cell lines to chemotherapy drugs, whereas blocking the mutant forms of p53 that inhibit p73 decreased resistance. The findings also partially resolve another mystery of chemotherapy--why chemotherapeutic agents are less harmful to noncancerous cells that naturally contain normal p53. "The fact that p73 levels are higher in cancer cells than in normal cells may be one of the reasons that cancer cells are more sensitive to DNA-damaging cancer drugs," Kaelin said. --Jennifer Frazer
Targets Found in Worm Insulin SignalingA team of scientists from HMS, Massachusetts General Hospital, and MIT has begun to identify the genes that are activated by the roundworm insulin receptor equivalent, DAF-2. Along with the transcription factor DAF-16, the receptor regulates longevity, metabolism, and development in a way analogous to their respective homologues in mammals. The team, led by Siu Sylvia Lee, HMS research fellow in genetics at MGH, published its results online in the April 10 Science. The team sought to identify the genes that DAF-16 regulates. "A transcription factor is only as important as its targets. The trick here was finding targets based on the recognition sequence, which was only eight bases," said Gary Ruvkun, senior author and HMS professor of genetics at MGH. Simply searching the Caenorhabditis elegans genome would have resulted in 3,700 matches just by chance. To narrow the field, the scientists searched both the fruit fly and worm genomes for recognition sequences in the 1 kb promoter region upstream of predicted genes, then compared results and identified orthologous genes. This reduced the number from 947 C. elegans genes to 17. To identify genes directly affected by the DAF-2 pathway, RNA expression of these genes was measured in animals deficient in DAF-2 and DAF-2/DAF-16. Six of the 17 genes were found to be expressed differentially. The scientists then used RNA interference to identify gene function. Two genes controlled lifespan, one affected fat storage, and three did not produce any detectable changes. The authors speculate that these three may be compensated for by other genes or may have subtle functions. "Like many genomic projects," said Ruvkun, "this is essentially generating a list that, once put together, will help us figure out how insulin signaling works." --Jennifer Frazer
Study Suggests Hypnosis May Benefit Wound HealingA small clinical trial performed with women who underwent breast reduction surgery has indicated that medical hypnosis may have contributed to quicker wound healing--even compared to a group that received supportive attention. This is the first randomized controlled study that has tested the ability of hypnotic intervention to accelerate healing of surgical incisions. Carol Ginandes, HMS clinical instructor in psychology in the Department of Psychiatry at McLean Hospital, and her colleagues studied 18 women scheduled to undergo reduction mammaplasty, who were randomly assigned to one of three groups--usual care only; supportive attention, in which patients received weekly support; and a hypnotic intervention group, in which patients received weekly hypnosis sessions from a study clinician who administered a standardized script composed by Ginandes. "I targeted what was going on biologically in wound healing week to week and created a sequence that would go along with it, emphasizing accelerated overall physical and psychological recovery as well as incision healing," she said. At one and seven weeks after surgery, a nurse and three physicians blind to patients' group assignments evaluated the incision conditions using the Wound Assessment Inventory. The nurse assessed this in person; the doctors from digital photographs. Patients also were asked to make self-assessments of healing progress and pain. The nurses' objective ratings showed the hypnosis group's wound healing to be significantly greater than that of the other two groups through 7 weeks (p < .001); the usual care control showed the slowest healing. The doctors' ratings and the patients' self-assessments did not reach statistical significance, although they all trended in the same direction. "Even in this small preliminary study, we seem to have evidence that a hypnotic protocol can augment normative wound healing. Although we are not advocating this particular application now, maybe with further research we could suggest it. In the larger sense, we were testing the hypothesis that mental input can actually influence physical healing," Ginandes said. The research appears in the April 2003 American Journal of Clinical Hypnosis. --Jennifer Frazer |
