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Matter Over Mind

Researchers Identify Gene Involved in White Matter Development

By Anna Miller

At first, Li-Jin Chew, Ph.D., research assistant professor of Pediatrics at the George Washington University School of Medicine and Health Sciences (SMHS), and Vittorio Gallo, Ph.D., professor of Pediatrics and of Pharmacology and Physiology at SMHS, were in the dark. Their eight-year venture to better understand how the brain makes and repairs myelin — a coating that insulates the axons of neurons and that, as a whole, is referred to as white matter — began slowly with little funding and few clues.

Li-Jin Chew and Vittorio Gallo
Li-Jin Chew, Ph.D., research assistant professor of Pediatrics at SMHS, and Vittorio Gallo, Ph.D., professor of Pediatrics and of Pharmacology and Physiology at SMHS

“At the beginning, there were many reasons we were crawling,” admits Chew, who is an investigator at the Center for Neuroscience Research at the Children’s Research Institute at Children’s National Medical Center (Children’s National), where Gallo is director and Wolf-Pack Chair in Neuroscience.

A break in the clouds came during an early screen, when the lab found that a gene called Sox17 was being regulated during myelination, or the formation of white matter. Although pinpointing this gene was no minor accomplishment (the finding was published in The Journal of Neuroscience in 2006), it left questions unanswered. What function did Sox17 have, and how does it work?

The researchers knew the answer wouldn’t come easy. The gene, which resides in many types of cells and is expressed only weakly and temporarily in developing white matter, is inherently difficult to study.

But recently, the Chew-Gallo team reached a major turning point in their research. In a study published online in the September 2011 edition of The Journal of Neuroscience, they identified Sox17 as a gene that helps direct immature brain cells (called oligodendrocyte progenitor cells) to mature and generate myelin through its regulation of the Wnt/betacatenin signaling pathway, a major pathway implicated in white matter development and in some forms of brain cancer. A glitch in these signals can result in mental retardation, developmental disabilities, and diseases of adult white matter such as multiple sclerosis.

“We were very excited because we were beginning to get a coherent picture of the interplay between these molecular mechanisms and the pathways that regulate oligodendrocyte development,” says Gallo. “The more we understand molecular mechanisms, the more we open our possibilities to target them with specific drugs.”

While the development of oligodendrocytes is studied widely, Chew and Gallo’s team is the only group to study Sox17’s role in this process. They are working toward renewing the NIH grant they were awarded five years ago, and are collaborating with researchers in France on a project funded by the National Multiple Sclerosis Society.

“We are very interested in expanding this study to understand the relevance of this gene in human cells and pathology,” says Gallo.

The success of the Chew-Gallo lab — which has trained top researchers in white matter development, including Jiho Sohn, Ph.D., who led the 2006 study as a GW graduate student and is now studying myelination as a postdoctoral fellow at the University of California, Davis, and Shibeshih Belachew, M.D., Ph.D., an initiator of the first screen who has since established the largest center for multiple sclerosis research and clinical care in Belgium — is attributable to teamwork and the robust environment for neuroscience research at Children’s National and at GW, home of the GW Institute for Neuroscience, they say.

“I think this study really exemplifies what we are all doing at GW and Children’s National,” says Gallo. “We are identifying mechanisms that might be used to manage abnormalities in disease.”

For more information about the Center for Neuroscience Research at Children’s National, visit www.childrensnational.org/research/OurResearch/centers/neuroscience/default.aspx.