Neurons in the brain and spinal cord, unlike those in the rest of the body, do not regenerate following injury. If you cut your finger, you’ll probably be able to use it again in a few days or weeks; if you sever your spinal cord, you’ll probably never be able to walk again.
Working with mice, researchers at Washington University School of Medicine in St. Louis have identified some of the critical stages taken by peripheral nerves (those in the arms and legs) as they regenerate. The findings outline a path that neurons in the spinal cord may be able to follow, perhaps leading to improved rehabilitation for those paralyzed by spinal cord injuries.
“We’ve figured out some of the events that are required for injured peripheral nerves to repair themselves, and we can see that these things fail to happen in the central nervous system. So now we’re trying to see if turning on these networks can help spinal cord neurons regenerate,”
said Valeria Cavalli, PhD, an associate professor of neuroscience.
Examining Peripheral Neurons
Every year, approximately 11,000 people in the United States survive a spinal cord injury. Car and motorbike accidents, falls, contact sports and diving, and firearms are the most common causes of such injuries.
Paramedics can limit the chance of further damage by immobilizing the spine immediately and gently, but there is no way to repair a spinal cord injury that has already happened. The neurons that make up the spinal cord do not repair on their own.
Except for their ability to regenerate, neurons in the central nervous system (the brain and spinal cord) and the peripheral nervous system are extremely similar. Cavalli realized that examining peripheral neurons could help explain why some injured neurons heal while others do not.
She resorted to a special type of sensory cell that can communicate with both neurological systems. These cells, known as dorsal root ganglion neurons, have long tendrils called axons and two offshoots. The axon connects to cells in the body’s periphery and can heal if cut; the other side connects to cells in the spinal cord and cannot recover after injury.
Selective Gene Expression
Cavalli and first author Young Mi Oh, PhD, a staff scientist, and colleagues grew mouse dorsal root ganglion neurons in the lab and then cut them to find out what biological processes occur as the cells regrow their axons.
In mice, they also severed the sciatic nerve, which goes up the leg and into the spinal cord via the dorsal root ganglia. The researchers then discovered a set of genes that required to be switched off in order for the axons to regrow.
“Other people also have shown that a big swath of genes is turned down during regeneration, but as a field we’ve just said, ‘Eh’ and ignored them to focus on the genes that are activated. Here, we showed that establishing a regeneration program means some genes have to be turned on but a lot have to be turned off,”
Cavalli said. In particular, a set of genes related to sending and receiving chemical and electrical signals — the primary duty of mature neurons — had to be silenced for the injury to heal, the researchers showed.
“The injured neuron has to stop functioning as a neuron and focus on repairing itself. This means the neuron has to transition back to an immature state so it can re-engage developmental programs and regrow,”
Cavalli said.
Regression Timing
The notion that cells must become less mature in order to regenerate is not novel, but Cavalli and Oh’s research lends weight to that notion. The researchers identified the essential biochemical and genetic players involved in regressing to a less developed state and demonstrated that the timing of the regression was critical to recovery success.
“If you’re triggering a system that makes the neuron less mature, you have to make sure it’s not forever,” Cavalli said. “It has to remain a neuron, albeit an immature one, so it can re-mature and start functioning again after it repairs itself.”
Cavalli and colleagues are working to gain a better understanding of when and for how long specific genes must be turned off, as well as whether silencing the genes in neurons from the central nervous system will cause them to regrow after injury.
“We haven’t found a cure, but we have a better understanding now of what injured neurons do. From here, we can build new hypotheses and work toward applying them to people,”
Cavalli said.
Abstract
Injured peripheral sensory neurons switch to a regenerative state after axon injury, which requires transcriptional and epigenetic changes. However, the roles and mechanisms of gene inactivation after injury are poorly understood. Here, we show that DNA methylation, which generally leads to gene silencing, is required for robust axon regeneration after peripheral nerve lesion. Ubiquitin-like containing PHD ring finger 1 (UHRF1), a critical epigenetic regulator involved in DNA methylation, increases upon axon injury and is required for robust axon regeneration. The increased level of UHRF1 results from a decrease in miR-9. The level of another target of miR-9, the transcriptional regulator RE1 silencing transcription factor (REST), transiently increases after injury and is required for axon regeneration. Mechanistically, UHRF1 interacts with DNA methyltransferases (DNMTs) and H3K9me3 at the promoter region to repress the expression of the tumor suppressor gene phosphatase and tensin homolog (PTEN) and REST. Our study reveals an epigenetic mechanism that silences tumor suppressor genes and restricts REST expression in time after injury to promote axon regeneration.
Reference:
- Young Mi Oh, Marcus Mahar, Eric E. Ewan, Kathleen M. Leahy, Guoyan Zhao, and Valeria Cavalli. Epigenetic regulator UHRF1 inactivates REST and growth suppressor gene expression via DNA methylation to promote axon regeneration. PNAS, 2018 DOI: 10.1073/pnas.1812518115
Last Updated on November 18, 2023