A violent fall, a vehicular accident, or a sports injury can sometimes damage the spinal cord and brain leading to paralysis and other life-threatening health problems. The nerve fibers that carry important information are unable to regrow, leading to irreversible damage. Using novel bioinformatics frameworks and screening platforms, researchers have now identified a new gene combination that can help enhance the growth of nerve fibers after an injury.
It is well known that mammals including humans show a high capacity for brain and spinal cord regeneration but only during young ages. The researchers set out to decode why and how young neurons respond so well to injury. They studied a class of genes called transcription factors. They identified a particular combination of genes KLF6/Nr5a2 that when expressed lead to enhanced growth of nerve fibers following injury.
If you think about growth after an injury, it is very similar to developmental growth that happens during the early embryonic stages. Inside the neuron, when you want an axon or nerve fiber to grow, there are networks of genes that work together. Between embryonic day 18 to about a week after birth, these genes are still on because they’re helping the axons grow. So, if an injury occurs during this period, the genes quickly deploy these networks to repair. But a week after birth, these genes are no longer active because active developmental axon growth has ended and they are no longer needed.
“So, if we are able to turn back these gene networks in response to an injury, then we have a chance for high regenerative success. We’re trying to artificially reboot those gene programs and trying to coax an older neuron to switch back to a younger, growth-competent state. And we do that by manipulating transcription factors that simultaneously regulate the expression of hundreds of growth-relevant genes because we can’t go in and tweak the expression of individual genes.
When asked if there is any evolutionary basis for these genes losing their program when we are adults scientist explains: “There could be a couple of reasons. One is we gave up or traded the ability to regenerate because even if these axons do regenerate, the chances of them reintegrating into a functional circuit in a complex system like the mammalian system is trickier. I also speculate that the longer the distance the axons have to grow, the more guidance errors can happen, and they can synapse onto the wrong targets leading to unintended behavioral outcomes.
The team adds that these findings can open up avenues to discover additional groups of transcription factors with stronger reprogramming abilities to ultimately allow us to fully revert an older neuron into a younger growth-competent state following injury. These findings also hold promise as a novel molecular strategy for the treatment of human spinal cord injuries in the future.
“We are continuing with pre-clinical tests of Klf6/Nr5a2, for example confirming the genes are still effective when delivered in the chronic injury state, many months after the initial damage. This information is critical for individuals now living with spinal injury.