Posts tagged axon regeneration
Articles and news from the latest research reports.
Existence of new neuron repair pathway discovered
Most of your neurons can’t be replaced.
Other parts of your body – such as skin and bone – can be replaced by the body growing new cells, but when you injure your neurons, you can’t just grow new ones; instead, the existing cells have to repair themselves.
In the case of axon injury, the neuron is able to repair or sometimes even fully regenerate its axon. But neurons have two sides – the axon (which sends signals to other cells) and the dendrite (which receives signals from other cells).
Melissa Rolls, an associate professor of biochemistry and molecular biology at Penn State and director of the Huck Institutes’ Center for Cellular Dynamics, has done extensive comparisons of axons and dendrites – culminating recently in a paper published in Cell Reports.
“We know that the axon side can repair itself,” says Rolls, “and we know a bunch of the molecular players. But we really didn’t know whether neurons have the same capacity to regenerate their dendrites, and so that’s what we set out to find in this study.”
“Our lab uses a Drosophila model system, where the dendrites are very accessible to manipulation,” she says, “so we decided that we would start by removing all the dendrites from the neurons to see if they could regenerate. We didn’t start with anything subtle, like taking off just a few dendrites. We said ‘Let’s just push the system to its maximum and see if this is even possible.’ And we were surprised because we found that not only is it possible, it’s actually much faster than axon regeneration: at least in the cells that we’re using, axon regeneration takes a day or two to initiate, while dendrite regeneration typically initiates within four to six hours and it works really well. All the cells where we removed the dendrites grew new dendrites – none of them died; so it’s clear that these cells have a way to both detect dendrite injury and initiate regrowth of the injured part.”
Age no obstacle to nerve cell regeneration
In aging worms at least, it is insulin, not Father Time, that inhibits a motor neuron’s ability to repair itself — a finding that suggests declines in nervous system health may not be inevitable.
All organisms show a declining ability to regenerate damaged nervous systems with age, but the study appearing in the Feb. 5 issue of the journal Neuron suggests this deficit is not due to the ravages of time.
“The nervous system regulates its own response to age, separately from what happens in the rest of the body,” said Marc Hammarlund, assistant professor of genetics and senior author of the new study. “By manipulating the insulin pathway, we can make animals that live longer but have nervous systems that age normally, or conversely, we can make animals that die at a normal age but have a young nervous system.”
Alexandra Byrne, postdoctoral associate in genetics and lead author of the study, identified two genetic pathways that regulate insulin activity and are responsible for age-related declines in a worm’s ability to regenerate neuronal axons, or connective branches. The team pinpointed two other pathways that also regulate a neuron’s ability to regenerate, but that have no connection to the age of the worm.
The worm C. elegans is a well-established model to study the genetics of aging, and manipulation of the family of genes that regulate insulin activity has been shown to dramatically increase lifespan of the organism. The new study reveals that insulin signaling is also directly affecting the nervous system.
“We hope to understand how different pathways coordinately regulate neuronal aging, and more specifically, how to entice an aged neuron to regenerate after injury,” Byrne said.
“The hope is to increase healthspan, not just lifespan,” Hammarlund said.
Turning back the clock on regeneration in neurons
When minor wounds heal, the fine nerve endings that sense touch, or control sweating, are usually able to regrow. Like many processes in the body, the ability to regenerate new tissues changes throughout the lifecycle, typically diminishing with age. To investigate the molecular details of regeneration, the nervous system of the worm, C. Elegans, is ideal because its entire blueprint—the connectome—is available. The close-knit cadre of researchers who study C. elegans are the true veterinarians of neuroscience in that they command nearly every tool in the field to study this microcosm of biology. Publishing today in Science, a group of these researchers has uncovered a genetic circuit that regulates the regrowth of axons after they are experimentally cut with a laser. While the integrity of these mechanisms insures stability in the adult nervous system, manipulation of them could allow insults to the system to be restored to normal function.
(C. Elegans neuron. Credit: Technion-Israel Institute of Technology)
In order to develop properly in the first place, the expression of the genes controlling tissue construction proceeds in a choreographed rhythm, with each having its proper time and place. Once the organism has developed, many of these genes are decommissioned, or their cycles of expression dephased. Sometimes two components that act together in the larval stage, oppose each other in the adult. Two players in this genetic tit-for-tat, lin-41 and let-7, have previously been found to act as timers during these transitions. The researchers in the study described here, stumbled upon this particular circuit while they were looking at the effect of yet another gene, alg-1, on axon regeneration. Specifically, they had found that worms with a mutant form of alg-1, could regenerate certain axons up to 2.5 times longer than the axons of normal adult worms.
One particular sensory neuron, the AVM (anterior ventral microtubule) neuron, has a clearly defined axon that can regrow in larva, in not in adults. This strangely-named neuron has an even stranger subcellular feature. Its dendrites, in addition to the axon, are filled with a unique kind of microtubule, one that is composed of 15 protofilaments. Most mammals use a microtubule form-factor specifically made from 13 protofilaments, but many invertebrates use anywhere from 10 to 15. The avm neuron is also unique in that is one of just a few neurons that migrates to an asymmetric position in the body of the worm—it has no counterpart on the opposite side.
(Let-7 microRNA. Credit: Wikipedia commons)
The AVM neuron shows clear expression not only the alg-1 gene, but also another factor regulated by alg-1 known as let-7. The researchers were able to show that let-7 is responsible for inhibiting adult regrowth in the AVM neuron. Inhibiting let-7 directly, or alternatively, increasing the level of its reciprocal inhibitor, lin-41, completely restored the regeneration capabilities of the larval axons. From this they conclude that cyclic interactions between let-7 and lin-41 are a general strategy used not only in determining cell fate in development, but also in controlling axon regeneration.
Expression of let-7 was controlled by using a version of the gene which is temperature-sensitive. The particular allele used has normal activity at 15 degrees C, but can be completely turned off at 20 degrees C. The actual product of the let-7 gene is ultimately not a protein, but one of a class of newly-discovered regulators known as microRNAs. The full functionality of microRNAs has yet to be completely defined, but they seem to be able to regulate proteins, DNA, and mRNA.
The researchers were also partial to speculation as to why the organism appears to take pains to inhibit regrowth in the adult. Axotomy by laser may not have been a primary selection criteria during the evolution of the worm, but some ability for tissue repair would be important in the life of a worm. In the greater scheme of things, it would seem that loss of certain capabilities in the adult, may be a small price to pay for the greater stability of connections that may come along with it.
We recently reported on a study in mice, which demonstrated that mature brains continue to remodel their fine structure throughout the entire life of the organism. Mammalian axons have the further complication that while myelination is required to conduct signals over appreciable distances, it can also be an impediment to regrowth. For axons that have been compromised by trauma, or through developmental fault, turning back the clock on a few genes may be only part of the puzzle.
(Source: medicalxpress.com)