2004 Directors' Summary Synopsis

AXON GUIDANCE AND SYNAPSE FUNCTION.

Research in the last decade has provided ample evidence that spinal cord axons can regenerate, however, questions still exist regarding how damaged nerve fibers can be "turned on" to grow, find their appropriate paths, know the distance they should grow, and when to stop growing and form connections. During embryonic development, a nerve cell’s ability to grow and find its connection depends on signals it receives from molecules found in the surrounding environment. One class of molecule, the cell adhesion molecules (CAMs), is particularly important in influencing developing nerve cells to extend their axons and find correct targets. Several CAMs, such as L1 and N-cadherin, have been shown to guide the growth of developing axons.

Dr. Vance Lemmon has been pursuing a thorough understanding of how the movement of L1 is controlled within nerve cells and signals them to find their paths. He has also pursued studies to identify molecules that work with L1. Recently, Lemmon found that for normal axon growth to occur, L1 must work with other membrane proteins and must link to actin inside axons, otherwise nerve branching does not occur properly. As a result of this line of research, the details of how L1 interacts with other molecules to influence axon growth and guidance is becoming better understood and may lead to the development of strategies to turn on and guide damaged axons.

Helping nerve fibers to find their targets is another important goal in regeneration research. Dr. John Bixby has studied the role that different types of CAMs known as receptor protein tyrosine phosphatases (RPTPs) have in guiding nerve fibers to their targets. When his lab inactivated RPTPs, they found that some axons did not grow to their proper targets. This finding suggests that RPTPs and other CAMs (like L1) work together to allow axon growth and to guide axons to appropriate targets.

Restoring function following SCI is also likely to require the reformation of synapses. Dr. Daniel Liebl has been studying the ephrins, another family of molecules that is not only important in axon guidance but is associated with the formation of the synapses. Dr. Liebl’s lab has evidence suggesting that a specific ephrin, ephrinB3, regulates the levels of important proteins within the synapse. In a recent experiment, when ephrinB3 was removed, they found the synapses were smaller in size and not as excitable. These results are leading them to believe that ephrinB3 may be important for the proper balance of proteins and chemicals at the synapse.

Understanding how synapses function, how nerve fibers are turned on and find their targets will be important in developing strategies to restore nerve pathways and promote return of function after SCI. As continuing studies are carried out, Miami Project researchers hope to further identify and characterize the various molecular and cellular interactions that regulate axon guidance and use this knowledge to develop novel treatments for regeneration after injury.