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Developmental Biology - Nerve Regeneration

How Fast Can Nerves Grow?

Research discovers a molecular process that controls the rate at which nerves grow...

Twenty million Americans suffer from peripheral nerve injuries, caused by traumas such as combat wounds, car and motorcycle crashes and medical challenges such as diabetes. Injuries can have a devastating impact on quality of life through loss of sensation, motor function and long-lasting nerve pain. Yet the body is capable of regenerating damaged nerves, however, the process is slow and often incomplete.
New research from the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA, has uncovered a molecular process controlling the rate at which nerves grow.

Nerve growth spurred during embryonic development and during recovery from injuries, can perhaps be maintained throughout life.

The study, led by senior author Samantha Butler and published in the Journal of Neuroscience, used experiments with mice to show it is possible to accelerate peripheral nerve growth by manipulating this molecular process. The finding could inform the development of therapies that reduce the time it takes for people to recovery from nerve injuries.
Our human nervous system is made up of:

• The central Nervous System - brain/spinal cord

• The Peripheral Nervous System - all other nerves

Peripheral nerves extend over long distances. They connect limbs, glands and organs to the brain and spinal cord. Nerves send signals that control movement via motor neurons that relay information — pain, touch, temperature — via sensory neurons.

Unlike nerves in our brain and spinal cord, which are protected by the skull and vertebrae, nerves of the peripheral nervous system are not protected, leaving them vulnerable to injury. While the body has a mechanism to help peripheral nerves reestablish connections after injury, this process is slow.
Damaged nerves regrow at an average rate of just one millimeter per day. This glacial pace can take a tremendous toll on people's lives, as they may have to live with impaired movement and sensation for many months or years.

"People with severe peripheral nerve injuries often lose sensation, which makes them susceptible to more injury. And, they lose mobility, which can lead to muscle atrophy. The process of nerve regrowth can be extremely painful and if muscles have atrophied it requires a lot of physical therapy to regain function. My lab seeks methods to accelerate this healing process." explains Samantha Butler, who holds the Eleanor I. Leslie Chair in Pioneering Brain Research in Neurobiology at the David Geffen School of Medicine, UCLA.
In a 2010 study in mice, Butler and her colleagues discovered they could control the rate at which nerves grow in the spinal cord during embryonic development through manipulation of the LIM domain kinase 1 gene, aka: Limk1.

Limk1 controls the rate of nerve growth by regulating the activity of a protein called cofilin.

Cofilin plays a key role in a process known as actin polymerization, or "treadmilling," which enables nerves to extend thread-like projections over long distances and form neural networks.

Butler's new paper builds on these findings by showing that Limk1 and cofilin also control the rate of growth of peripheral nerves during both development and regeneration.

"We discovered that one of the first things a nerve does after injury is switch on all these early developmental molecules that controlled how it grew in the first place," said Butler, who is a member of the UCLA Broad Stem Cell Research Center. "It's somewhat similar to how an adult in crisis might reach out to their childhood friends to renew themselves."

In preclinical tests using mouse with peripheral nerve injuries, Butler's team showed this molecular process can be manipulated to make nerves grow faster. Specifically, they found mice genetically engineered with the Limk1 gene removed exhibited a 15% increase in speed of nerve regrowth following injury.
"This is a modest improvement for a mouse but one that could translate into a major improvement for a human because our nerves have so much farther to grow."

S. J. Butler, Department of Neurobiology, Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, California, USA, who notes how nerves regrow at the same rate in both mice and humans.

This increased rate of nerve regrowth resulted in faster recovery of both motor and sensory functions as measured by how fast the injured mice regained the ability to walk and the sensation in their paws. This is significant because sensory function can take longer than motor function to recover after a traumatic injury, yet sensory function is critical to quality of life.
As a next step, Butler and her lab are using human stem cell-derived motor neurons to screen for drug candidates that could modify this molecular process and speed nerve regeneration in humans. They are also expanding the scope of their study by examining if adding more cofilin - rather than inhibiting Limk1 - could be even more effective in speeding up recovery from peripheral nerve injuries.

The experimental treatment model described here has onlybeen tested pre-clinically. It has not been tested in humans nor approved by the Food and Drug Administration as safe and effective in humans.

Regenerating axons often have to grow considerable distances to reestablish circuits, making functional recovery a lengthy process. One solution to this problem would be to co-opt the “temporal” guidance mechanisms that control the rate of axon growth during development to accelerate the rate at which nerves regenerate in adults. We have previously found that the loss of Limk1, a negative regulator of cofilin, accelerates the rate of spinal commissural axon growth. Here, we use mouse models to show that spinal motor axon outgrowth is similarly promoted by the loss of Limk1, suggesting that temporal guidance mechanisms are widely used during development. Furthermore, we find that the regulation of cofilin activity is an acute response to nerve injury in the peripheral nervous system. Within hours of a sciatic nerve injury, the level of phosphorylated cofilin dramatically increases at the lesion site, in a Limk1-dependent manner. This response may be a major constraint on the rate of peripheral nerve regeneration. Proof-of-principle experiments show that elevating cofilin activity, through the loss of Limk1, results in faster sciatic nerve growth, and improved recovery of some sensory and motor function.

Significance Statement
The studies shed light on an endogenous, shared mechanism that controls the rate at which developing and regenerating axons grow. An understanding of these mechanisms is key for developing therapies to reduce painful recovery times for nerve-injury patients, by accelerating the rate at which damaged nerves reconnect with their synaptic targets.

M.E. Frendo, A. da Silva, K. D. Phan, S. Riche and S.J. Butler.

Funding for this study was provided by the National Institutes of Health, the Craig H. Neilsen Foundation, the Merkin Family Foundation and the UCLA Broad Stem Cell Research Center Research Award Program, supported by the Jean Perkins Foundation.

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Oct 9 2019   Fetal Timeline   Maternal Timeline   News  

Regenerating nerves

LEFT Image of post-natal mouse spinal cord with the protein cofilin in RED.
RIGHT Image - Cofilin (RED) is inactivated by the gene Limk1.
Neurons in GREEN, motor neurons in BLUE.
CREDIT Broad Stem Cell Research Center.

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