Breaking New Ground in Gray Matter

In the black-and-white video image playing on Le Ma’s computer, small tentacles grow quickly outward, branching like tree limbs from a central white sphere. Some of the wispy lines contract and disappear, some stretch and swell and connect with other branches.

The time-lapse light microscope video is over in less than 10 seconds. What it shows – the intricate, dynamic formation of connections between brain cells – occurs throughout the development and still goes on in our brain for a lifetime. From his lab in the Zilkha Neurogenetic Institute, Ma, assistant professor of cell and neurobiology in the Keck School of Medicine of USC, is breaking new ground in the quest to understand just how the brain works. His research is focused on understanding what triggers the network-building that goes on in billions of nerve cells in the developing brain. “We know how a computer works and how individual building blocks are connected to form circuits,” said the young researcher, who came to USC six months ago from Stanford University. “What we don’t know is how individual nerve cells make thousands of connections to establish the complex networks in the brain. These connections are established during embryonic development and any misregulation could fail to form functional circuits and ultimately lead to early childhood diseases such as mental retardation.” In addition, he said, while the connections in a computer, once built, remain essentially the same, the brain has the remarkable ability to “remodel” the connections even after the networks are established. “Such ability appears to be diminished over time in the central nervous system, contributing to the great medical challenge in adult nerve regeneration,” he said. “If we could learn how to trigger that remodeling, or better yet, how to direct it, it could have enormous medical implications.” It has been well understood that neurons connect with other partners through axons and dendrites, the long processes from nerve cell bodies, Ma said. A great deal has been learned in the past 15 years about how those processes are guided to different locations. What is not known, however, is how they are generated to form the most diverse branched cells of the body, which were documented by Ramon y Cajal more than 100 years ago. Ma listed additional questions: “How does the neuron decide when and where to make branches? What controls the branch number and pattern? How is it regulated coordinately with neurite growth and guidance to produce many striking cell morphologies in our body? How are they modified in learning and memory?” he asked. To address these questions, Ma focuses on sensory neurons in the dorsal root ganglion as a model and studies their branch formation by combining a variety of approaches, including transgenic mice, primary cell culture and live cell imaging. “The advantage of these approaches is that it gives a whole system to study the branching process from molecules to animals,” he said. Using these modern tools, Ma and his former mentor Marc Tessier-Lavigne discovered two genes that change cell shape and make different branches. One is the secreted molecule “Slit” and the other its cell surface receptor “Robo.” These signaling molecules, Ma said, “which are known for their ability to tell the branches which direction to go, can also tell the cells where and when to make branches.” Interestingly, Ma found Slit and Robo are not just used in the nervous system – withdrawal of either one causes growth defects in other organs such as kidneys or hearts. The molecules are also used in blood vessel formation, Ma said, “which connects with angiogenesis in cancer. If you think about it, the blood vessels are another type of branched networks, but it is really fascinating how the same genes control two branched networks that are completely different in their size scales.” In addition to working on these molecules, Ma is focused on identifying other genes that play a role in neurite morphogenesis. “Once you know the genes, you can see how they work together to build these thousands of different cell morphologies,” he said. “Gene discovery is a useful tool to help understand the process completely.”(Source: Monika Guttman: April 2006.)