"This study illustrates the way in which dissecting a basic problem in developmental biology can lead to unexpected connections to human disease," said Dr. Eric Olson, chairman of molecular biology and senior author of the study, which appears in today's issue of Cell.
"Who could have ever anticipated that studying an ancient gene that regulates muscle development in fruit flies could provide a window into understanding a wasting disorder in humans? That's really the beauty of biology and one of the gratifying aspects of this project for us," he said.
Olson and his colleagues are examining the evolutionary conservation of developmental mechanisms, focusing specifically on muscle development and how a gene in a fruit fly can play the same function in a mouse. One gene, known as twist, encodes a gene-regulatory protein controlling muscle formation in fruit flies, and the researchers' initial hypothesis was that the function of the gene in both organisms would be identical.
But after four years of study, the researchers found otherwise. Unexpectedly, mice genetically engineered to lack twist were underweight, frail and developed cachexia, a severe wasting disorder commonly associated with cancer, AIDS and chronic infection in humans.
"The role of twist as a regulator of muscle development had been well-established in fruit flies by several groups, including our own, but the functions of the mammalian gene were not known," said Olson, director of the Nancy B. and Jake L. Hamon Center for Basic Research in Cancer and the Nearburg Family Center for Basic Research in Pediatric Oncology. "We assumed it would play a role similar to the fruit fly gene in controlling muscle development, but what we discovered was a completely unanticipated function for this ancient gene."
Last month, UT Southwestern researchers led by Olson reported in the Dec. 20 issue of Science the discovery of two unique factors in the development of specific facial muscles that could aid in the study and treatment of muscle diseases.
"The Science study is interesting because it begins to shed some light on a set of genes specifically required for forming the muscles of the face," Olson said. "Our goal is to find the other genes they regulate and that regulate them."
Earlier research had demonstrated that the MyoD family of basic helix-loop-helix (bHLH) transcription factors (proteins that act as on/off switches for various genetic programs) controls the formation of all skeletal muscles in vertebrates. But little is known of the molecules or mechanisms that confer unique identities to different types of skeletal muscles.
Knowing that the MyoR and capsulin genes are related bHLH transcription factors in facial muscles, the researchers showed that specific facial muscles are missing in mice lacking both of these factors. This reflects the absence of MyoD family gene expression and removal of the corresponding muscle lineages.
The findings reported in Science demonstrate MyoR and capsulin play an important role in the development of specific head muscles, which eventually could help in the understanding and treatment of muscle diseases.
In the most recent study, twist's connection with cachexia continues that battle against debilitating diseases. According to the National Association of Veterans' Research and Education Foundations, cachexia affects about half of all cancer and HIV patients, as well as those with bacterial and parasitic diseases, rheumatoid arthritis, and chronic diseases of the bowel, liver, lungs and heart.
Cachexia is triggered by cytokines, a family of circulating proteins. The researchers found that mice lacking twist showed highly elevated levels of cytokines because twist normally binds to the cytokine genes' control regions and shuts them off.
The absence of twist means the cytokines cannot be turned off. Instead, they become over-expressed, eventually leading to cachexia, Olson said.
Dr. James Richardson, professor of molecular biology and pathology and a study author, said the discovery that twist down-regulates certain cytokine pathways is important, as cytokines are also involved in chronic inflammatory diseases such as arthritis and asthma, and also have been implicated in neurodegenerative diseases.
"Understanding the role of twist in the negative regulation of proinflammatory cytokines offers opportunities to design drugs to modulate cytokine expression in man," Richardson said.
This latest finding on the twist gene provides scientists valuable information toward the development of more specific and potent drugs for treating cachexia, cancer and other conditions, Richardson said.
The research was supported by grants from the National Institutes of Health.
Other contributors to the Cell study were Drazan Sosic, molecular biology graduate student research assistant, and researchers from Washington University School of Medicine in St. Louis.
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