Apr. 4, 2002 BOSTON -— Researchers at Dana-Farber Cancer Institute have found that a pair of recently discovered genes enables the brain of vertebrate animals, including humans, to grow large and complex.
The findings, published in the April 5 issue of Cell, shed light on how the Olig 1 and Olig 2 genes direct the formation of a key type of supporting cell required by nerve cells to transmit their signals efficiently over long distances. (Cell selected the study for early publication and has already posted the paper on its Web site.) Called oligodendrocytes, these cells wrap a kind of biological insulation around nerve cells. By learning how oligodendrocytes normally develop, scientists say they may uncover clues to diseases ranging from multiple sclerosis to mental retardation to brain tumors. The earliest fruits of the work may include more accurate diagnosis of certain brain tumors, say the researchers.
“We reason that some of the genes required to develop a normal, functioning brain may contribute to cancer of the brain if their expression is perturbed by mutation,” says Charles Stiles, PhD, co-chair of the Cancer Biology Department at Dana-Farber and one of two senior authors on the paper. “With the discovery of new cancer-causing genes comes the opportunity to develop ‘smart drugs’ that can now be directed towards cells that express these mutant genes.”
Stiles and David Rowitch, MD, of the Dana-Farber Department of Pediatric Oncology, directed the team of researchers that is studying the genetic basis of brain and central nervous system development to gain insights into brain cancer.
The brain and spinal cord are made up of three principal kinds of cells. Neurons, along which nerve impulses flash, are the most important but by far the least numerous. Much of the brain and spinal cord consists of glial cells, mainly oligodendrocytes and astrocytes, which support and nourish neurons. It’s believed the brain has about 100 billion neurons and five to ten times as many glial cells. Most brain tumors occur in the glial cells. Genes control how the precursor cells develop into the different types of cells.
The oligodendrocyte, a cell in which an Olig gene is expressed, is an important glial cell that carries out a key function in the newly formed brain. Oligodendrocytes, acting like molecular electricians, wrap the long, thread-like neuron with a sheath of myelin, a fatty material that acts like insulation around an electric wire, enabling it to transmit nerve messages at high speed and over long distances. In “demyelinating” diseases like multiple sclerosis, nerves lose their myelin coating and can’t transmit commands to the muscles as effectively.
Q. Richard Lu, PhD, a postdoctoral researcher in Stiles’ laboratory and the paper’s lead author, led a team that cloned the Olig genes in 2000, but at that time their function wasn’t clear. These latest findings by Stiles, Rowitch and their colleagues show the unanticipated breadth of Olig gene functions during the development of the spinal cord.
To figure out the genes’ normal duties, the investigators bred laboratory mice that lacked either one or both of the genes – a so-called “gene knockout” experiment. (The knockouts of both genes at once were done by scientists at the California Institute of Technology, who are publishing their results separately in the same issue of Cell.) When either the Olig 2 or both genes were absent, the embryos failed to generate any oligodendrocytes in the spinal cord. In addition, the embryos developed no motor neurons, the particular neurons that control muscle movement. As a result, the newborn mice were totally paralyzed.
“The findings show that Olig genes serve pivotal functions in the organization of the developing central nervous system,” said Rowitch. “The work has important implications for understanding diseases of newborns in which motor neuron function is lacking, and may provide insights into recovery from spinal cord injuries.”
This outcome was surprising to the researchers because it demonstrated that neurons and oligodendrocytes are more closely related than had been thought. Until now the assumption was that oligodendrocytes developed from precursor cells that also gave rise to astrocytes – another type of supporting cells – and that neurons developed independently.
“This work calls for some significant rethinking in developmental neurobiology,” said Stiles. “Our data show clearly that oligodendrocytes are more closely related to neurons – specifically motor neurons – than to astrocytes.”
One near-term payoff from the work is the potential for the genes to serve as markers for certain brain tumors involving oligodendrocytes. “There is not currently a good marker for this kind of tumor, called an oligodendroglioma, but it is important to identify it since it can usually be treated effectively,” explains Peter Black, MD, a neurosurgeon at Brigham and Women’s Hospital who was involved in the previous work that led to the discovery of the Olig genes. Black adds that the new findings “conceptually change our thinking of the way the nervous system develops.”
The strategy of studying normal development of cells to gain clues about cancer “is an exciting approach” that may lead to progress in the frustrating battle against brain tumors, says Rowitch. “Brain tumors are the most therapy-resistant of cancers,” he said. “There must be something different about their biology, and this strategy may give us new insights into the biology of brain tumors.”
The research was funded by the Dana Farber/Mahoney Center for Neuro-Oncology, the National Institutes of Health and the National Multiple Sclerosis Society. The Dana Farber/Mahoney Center for Neuro-Oncology was established two years ago to search for new treatments for brain tumors and other nervous system malignancies by identifying and cloning the genes that direct the formation of the normal brain, since those genes, when abnormal, give rise to cancer.
The paper’s other authors are Tao Sun, PhD, and Zhimin Zhu, PhD, of Dana-Farber, and students Nan Ma, and Meritxell Garcia, who were formerly at Dana-Farber.
Dana-Farber Cancer Institute (http://www.danafarber.org) is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), designated a comprehensive cancer center by the National Cancer Institute.
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