Marc Hammarlund uses C. elegans as a model to investigate axonal regeneration. C. elegans is transparent, so it is easy to see individual neurons and axons in vivo when they are tagged with fluorescent GFP. (Source: Marc Hammarlund)
On Friday, September 25, 2015, Yale professor Marc Hammarlund gave a lecture at Dartmouth College on axonal regeneration in C. elegans. Axons are long, slender projections from a neuron that conduct electrical signals essential for neuronal function.
Dr. Hammarlund’s lab explores the post-development nervous system, namely maintenance of neuronal structure and function, aging, and injury and repair. He has also discovered many genes involved in axonal regeneration after neuronal injury, which have important implications for both basic and clinical research on the nervous system.
The human nervous system is by far the most complex organ system in the body and takes four years to develop. However, we spend the remaining 95 percent of our lives with a post-development nervous system that regulates everything from our behavior to our learning and memory. In the past, the scientific community believed that the nervous system remained essentially unaltered after its initial development.
Recent research, including Dr. Hammarlund’s work, has flipped this paradigm on its head. Neurons are extremely delicate and vulnerable to damage, with axons over a million times longer than they are wide. Since the nervous system lacks neural stem cells, neurons must be able to regenerate in order to maintain their structure and function over their long lives.
Dr. Hammarlund investigates this line of research using genetic screens and engineering in C. elegans. His lab found that damaged axons trigger an injury response that stimulates an axonal “growth cone” that regrows a functionally intact axon with a 70 percent success rate in wild type C. elegans. By researching the mechanisms behind this regeneration, Dr. Hammarlund hopes to find ways to make axonal regeneration more successful.
His lab used C. elegans mutants with mostly regenerated nervous systems (due to spontaneous axon breakage) to run an unbiased genetic screen for axon regeneration genes. After feeding bacteria expressing double-stranded RNA with altered genes to these C. elegans mutants, Dr. Hammarlund discovered which genes are essential for normal axon regeneration. He next discussed two different genes, dlk-1 and RtcB-1, which affect axon regeneration in different ways.
Dr. Hammarlund’s most recent unpublished research involves the gene RtcB-1. His lab discovered that the axon regeneration success rate skyrockets from 70 to 95 percent with a mutation of RtcB-1. This surprised the researchers, as RtcB-1 encodes an RNA ligase with a known role in tRNA maturation — not exactly related to axon regeneration. His lab is currently researching RtcB-1’s role in other RNA ligations, such as for mRNA.
On the other hand, the dlk-1 gene is not required for nervous system development, but it is essential for axonal regeneration. It must be present at the time of axonal injury for any axonal regeneration to occur, and it boosts the regeneration rate to 100 percent, with an almost instant “growth cone,” when it is overexpressed in C. elegans.
Dr. Hammarlund’s lab discovered that among other functions, the dlk-1 gene helps regulate neuronal levels of poly(ADP-ribose) polymerases, or PARPs, which play a role in DNA damage responses, neurodegeneration, apoptosis, and cancers. Dr. Hammarlund’s lab discovered that PARP inhibitors, currently in clinical trials as cancer drugs, improve axon regeneration and functional recovery in GABA neurons.
Amazingly, the dlk-1 gene is also found in Drosophila and mice, demonstrating that axonal regeneration is an evolutionarily conserved process that occurs via a similar mechanism in many different species. Dr. Hammarlund’s research may therefore have clinical applications for restoring neuronal function in humans after injury.
References:
1). Hammarlund, M. (2015, September 25). Mechanisms of axon regeneration. Lecture presented at Cramer Seminar in Dartmouth College, Hanover, NH.