Our group engages in advanced research in regenerative neuroscience from the molecular to cell biological and integrative levels. A key research goal is to understand the mechanisms underlying the guidance of nerve growth in the developing and regenerating nervous system. Within this theme, specific topics under investigation include molecular analysis of receptors and signal transduction mechanisms; axon guidance, target recognition and regeneration; formation and plasticity of synapses; and development of neural networks. Related topics we are investigating are the regulation of glioma cell motility and mechanisms controlling vascular development and regeneration. The lab offers an integrated approach to training in modern neurobiology, utilizing molecular, biochemical and cell biological techniques as well as advanced optical imaging. Members of the lab have the opportunity to work closely with the Spinal Cord Injury research team at Mayo.
Axon guidance and regeneration
Our research goal is to understand the mechanisms underlying the guidance of nerve growth in the developing and regenerating nervous system. During embryonic development, newly born neurons extend neurites that can grow long distances to reach target cells, thus establishing the intricate wiring of the nervous system. Growth cones at the tips of growing neurites guide this process by sensing attractive and repulsive cues in the immediate environment and transducing guidance information into intracellular signals to induce growth and directed motility. Unfortunately, relatively little is known about these signals or the molecular identity of downstream effectors that mediate either attraction or repulsion. Our studies utilize a relatively simple model system to characterize the intracellular signaling events that mediate the guidance of nerve growth. We grow neurons in cell culture from embryonic central nervous system tissue that is isolated from rats, mice and Xenopus tadpoles to observe their directed growth and intracellular signaling events with varying conditions. We hope that by better understanding these processes in the normal developing nervous system, we will gain insight into methods that can be used to overcome inhibition to nerve growth in the adult central nervous system.
Ca2+, cAMP and cGMP signaling
Our work has shown that extracellular guidance cues can induce an intracellular gradient of the second messenger Ca2+ in the growth cone, and that both cyclic nucleotides and neuronal activity can modulate these Ca2+ signals to convert growth cone repulsion to attraction. We found that it is the magnitude of Ca2+ signal that specifies either attractive or repulsive growth cone turning, presumably depending on the activation of distinct downstream effectors. We also found that migrating growth cones can adapt to their environment, undergoing consecutive phases of desensitization and resensitization in the presence of increasing basal concentrations of guidance factors. Desensitization is accompanied by a reduction of Ca2+ signaling, whereas resensitization requires local protein synthesis and activation of a specific enzyme called mitogen-activated protein kinase. Such adaptive behavior allows the growth cone to readjust its sensitivity over a wide range of concentrations of the guidance factor, an essential feature for long-range directed motility. The mechanism of this adaptive process remains to be fully elucidated. We hope that by better understanding these processes in the normal developing nervous system, we will gain insight into methods that can be used to overcome inhibition to nerve growth in the adult central nervous system. This approach holds great promise, since many repulsive guidance factors also inhibit nerve growth and regeneration. Thus, methods that modulate intracellular signals and convert growth cone repulsion to attraction may also promote regeneration, thereby providing insight into potential therapeutic approaches for enhancing nerve regeneration in the brain and spinal cord following degeneration or injury.
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