Investigating Mechanisms of Axon Regeneration

How do adult neurons repair themselves after injury or disease? While young neurons are able to regenerate damaged axons, one of the earliest consequences of age in neurons is a loss of regenerative ability. We found the loss of regenerative ability in aging neurons is not merely a secondary consequence of a decrepit organism, but a genetically regulated process. We aim to understand the genetic and cellular mechanisms that regulate an adult neuron’s ability to repair itself and regain function after injury or neurodegenerative disease.

Our approach is to 1) identify mechanisms that regulate regeneration of adult axons with functional genomics, and 2) functionally characterize identified mechanisms with detailed genetic analyses, cell biology, chemical genetics, laser axotomy, imaging, and behavioral assays. Our investigations are largely carried out in C. elegans, a model in which conserved regulators of axon regeneration are studied in vivo and in a matter of days.  This work will significantly enhance our understanding of how to elicit regeneration and restore function to damaged neurons. Moreover, since regulators of regeneration, including DLK and PTEN, are conserved between C. elegans and mammals, our findings may contribute to improved therapies for spinal cord injury and neurodegenerative disease.

Investigating axon regeneration in C. elegans

The worm has a transparent cuticle, invariant nervous system, short 3-day life cycle,and a well-characterized, largely-conserved genome. These features allow the mechanisms that regulate axon regeneration to be studied in vivo with single-cell resolution. In a typical experiment, individual GABA neurons expressing GFP are severed with a pulsed laser and axon regeneration is scored 24-48 hrs later. Since 70% of axons regenerate in a wild type worm, both positive and negative effects of genetic mutations or chemical exposure can be determined with this system. The image depicts a worm with two severed GABA axons, one of which is not regenerating (blue box) and one that is (red box).