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Dennis D. M. O'Leary

 

Dennis D. M. O'Leary

Dennis D. M. O'Leary

Professor
Molecular Neurobiology Laboratory

"We believe that identifying the mechanisms underlying developmental events is the only way to understand the basis of any biological disorder and to gain insight into how one might repair damage to the nervous system due to genetic defects, tumors, or injuries to the brain or spinal cord."

Neurons constituting the optic nerve wire up to the brain in a highly dynamic way. Cell bodies in the developing retina sprout processes, or projections, called axons, which extend toward visual centers in the brain, lured by attractive cues and making U-turns when they take the wrong path. Understanding how they find their targets so accurately is not only a central question of neuroscience today, but it is crucial to repairing defective nerve connections with the help of stem cell therapy.

In a recent study, O'Leary and his team identified an unanticipated factor that helps keep retinal axons from going astray. The first hint came from mice genetically engineered to lack p75, a protein previously known to regulate whether neurons live or die. When retinal axons migrating toward the visual cortex reached their first rest stop in these mice, they docked slightly short of their destination, like a train halting shy of the platform. This migration error in p75-minus mice was puzzling: Researchers have studied p75 for decades and found it associated with activities as varied as neuronal growth, survival, and regeneration. But axonal migration was not among them.

The observed effect, however, was reminiscent of defects seen when a gene called Ephrin-A is missing in the retina. Unlike p75, Ephrin-A is a well-characterized sender and receiver of axon guidance signals, but it lacks appendages normally seen on proteins initiating cell migration; p75, however, displays those elements, suggesting that the proteins pair up—one receiving the migration signal and other transmitting it. Upon closer investigation, the researchers found Ephrin-A and p75 complexes in axonal membranes and showed that, when activated, they could provide the kind of biochemical kick required to turn a moving axon around. This explained why retinal neurons missed the target in the p75-minus mice: They simply lacked the cellular machinery to respond to critical repellant signals encountered en route to the brain and stopped migrating prematurely.

Lab Photo

Left to right:
Standing: Yoo-Shick Lim, Andreas Zembryski, Scott May, Todd Kroll, Carlos Perez-Garcia, Shen-Ju Chou, Todd McLaughlin, Axel Leingartner, Zoila Babot Sitting: Berta Higgins, Haydee Gutierrez, Dennis O'Leary, Suzanna Chan, Setsuko Sahara

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Dennis D. M. O'Leary

Faculty

Dennis D. M. O'Leary

Dennis D. M. O'Leary

Professor
Molecular Neurobiology Laboratory

Dr. Dennis O'Leary, a Professor in the Molecular Neurobiology Laboratory, studies development and plasticity of the vertebrate nervous system. Among the issues that Dr. O'Leary's research team focuses on are: (1) forebrain development and patterning, especially the specification and differentiation of the functionally specialized areas of the cortex and related parts of the brain and spinal cord, and (2) axon guidance and development of neural maps, particularly between the eye and the brain. His group also have strong interests in stem cell biology and the effects of developmental plasticity on behavioral performance. Among their findings is the first demonstration of the genetic control of area patterning of the neocortex and the genes that specify the identities of the primary areas that process sensory information and control motor output. In addition, Dr. O'Leary's group has defined roles for the first guidance molecules that control the development of neural mapping, the Ephs and ephrins. Their work has made novel relationships between neural plasticity and behavioral performance. Dr. O'Leary's goal is to understand fundamental developmental events, and to use this knowledge to make the most efficient theraputic use of stem cell biology and to design effective strategies to overcome birth defects, neurological diseases and disorders, and neural injury.

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