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| Dean Reinke Deans' Stroke Musing |
Fascinating stuff. If we had anything close to a fucking decent stroke association this would be added to one of the strategies requiring followup and foundation grants to get researchers to study this in humans. This is so god-damned brain dead simple. But I don't think we have anyone in the stroke medical leadership that has two functioning neutrons. You're fucking screwed if you have a stroke anytime in the next 50 years. More wonderful stuff from the Dana Foundation - Clue to Brain Regeneration Discovered in Lab Mic
A salamander can lose a limb or an eye and grow it back, nerves and all. A gecko can detach its tail on purpose—a great way to spoof a pursuing predator—and a new one will sprout in weeks. A zebrafish can regenerate missing parts of its heart and brain. Unfortunately we mammals just aren’t very good at regrowing lost bits. Medicine would be transformed if we could find a way to surmount this limitation, particularly in the central nervous system (CNS), where regeneration is heavily restricted.
Among the more promising leads turned up recently is a finding from Harvard researchers, published online in May, that hints at a way to boost the regeneration capacity of CNS axons—nerve fibers that are often damaged in brain injuries and neurodegenerative diseases. Therapies that exploit the new finding are years away at best, but might end up being applicable to a variety of common, debilitating conditions, from strokes to Alzheimer’s and Parkinson’s.
“We’re pretty confident in this being quite a big deal,” says Harvard’s Michael Costigan, who was co-senior author of the study, along with Clifford J. Woolf.
The Outlier
The researchers discovered the clue to improved axonal regeneration by looking at different strains of lab mice, to see which strain could regenerate its CNS axons better than the others. The nine strains selected are part of a set called the Collaborative Cross, which covers most of the genetic variation in mice and is commonly used by biologists to study the effects of gene mutations.
In an initial experiment, lead author Takao Omura harvested sensory neurons from the spines of the mice, and cultured the neurons in the presence of CNS myelin—a protein that normally sheathes CNS axons and also contains natural inhibitors of CNS axonal growth.
Sensory neurons like these have, so to speak, one foot in the central nervous system and the other in the peripheral nervous system, where regeneration is somewhat less restricted. A two-branched axon normally extends from the cell body of such a neuron, one being the “peripheral branch” that runs to its stimulus-sensing nerve end in the skin, bone, muscle, or other organ. The other, “central branch” sends sensory signals brainward via the spinal cord. The central branch is considered part of the CNS, yet it often does grow slightly longer after the peripheral branch is injured.
Omura and his colleagues found that one strain, known as CAST/Ei, stuck way out from the others in its ability to lengthen sensory neuron central branches following peripheral branch injury, and despite the presence of myelin-based growth inhibition.
“It was nothing like what you’d see in a normal lab mouse,” says Omura.
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| Image courtesy of Neuron, Omura et al |
Remarkably, Omura found that in lab dish tests without CNS axon-regrowth inhibitors, the central branch axons of pre-injured sensory neurons grew longer in the other strains too, so that the growth seen in CAST/Ei mice was no longer dramatically greater. That result suggests that the key difference in CAST/Ei mice is not a broadly higher propensity for axonal growth, but a specific ability to overcome the growth-inhibiting environment of the adult CNS.
Moving beyond lab-dish tests, Omura conducted tests in live mice of spine damage, optic nerve crush, and stroke, and confirmed in each case that CAST/Ei neurons have an unusually strong ability to regrow their axons despite the inhibitory environment of the CNS, when they are pre-conditioned with a mild injury.
The average axonal regrowth in the CAST/Ei mice in these in vivo experiments, says Omura, “was at least several times what we saw in the C57BL/6 comparison strain.”
Is Activin the Answer?
To find the source of this dramatically increased regenerative capacity, Omura and colleagues looked at neuronal gene expression patterns across the different strains. The gene whose expression seemed most tightly linked to CAST/Ei axonal regeneration in the presence of myelin turned out to be Inhba—which codes for a subunit of a protein called Activin.
Activin is involved in development, wound-healing, and other pro-growth functions. Prior studies have linked it to fin regeneration in zebrafish and tail regeneration in geckos.
Remarkably, levels of Inhba gene transcripts in sensory neurons jumped after injury only in the CAST/Ei mice, but not in other strains, and not in a rat that was also tested. That result suggested that CAST/Ei mice uniquely overproduce Activin after nerve injury, and the increased Activin signaling—possibly with other factors—somehow helps negate the usual growth-inhibitory environment.
To confirm the role of Activin signaling, the researchers blocked it in pre-conditioned, myelin-cultured neurons from the CAST/Ei mice, using an Activin receptor antagonist compound, and observed a major reduction in new axonal growth. Conversely, adding Activin proteins to myelin-cultured neurons from a more standard mouse strain caused ten times as many neurons to extend their axons, and boosted the average length of the new growth by a factor of nearly four. A preliminary test also indicated that Activin can have a similar growth-permitting effect in injured retinal neurons from rats.
Activin is part of a family of proteins that signal via the same set of receptors and have functions that aren’t fully understood. Intriguingly, the “fountain of youth” protein GDF11, recent results for which have drawn controversy—some say it is a regeneration booster, others a regeneration inhibitor—also appears to signal through Activin receptors.
Costigan says that he and his lab are now trying, “step by step,” to discover the precise mechanisms that confer a greater axonal regeneration capacity on CAST/Ei mice.
What Makes CAST/ei Mice so Special?
One of the questions raised by the findings is: how did the CAST/Ei mice end up with this striking capacity for CNS axon regeneration whereas the other tested strains don’t have it?
“I think it was just chance genetic variation that was fixed in that inbred strain,” says Greg Cox, a researcher at The Jackson Laboratory, which created the CAST/Ei strain and others used in the study.
Cox points out that inbred mouse strains often vary greatly in their genetic backgrounds, disease susceptibilities, behaviors, and so on—comparable to the variation seen in the human population.
Omura nevertheless wonders whether CAST/Ei mice are less unique than they seem. Most lab mouse strains are derived from long-domesticated “fancy mice”—essentially pets and show-animals. (Humans have been keeping mice as pets for centuries.) But the “founder” animals used to make the CAST/Ei strain were wild mice trapped by an American researcher in a grain warehouse in Chonburi, Thailand, around 1970. (CAST refers to the castaneous, or chestnut color of the animals, and Ei refers to Eva Eichler, the Jackson Laboratory researcher who bred the strain in 1971.)
“They do act wild,” says Costigan. “They jump around a lot and they’re very fast.”
Conceivably, greater axonal regeneration capacity was an important trait to have in the much harsher wild-mouse environment, and would be seen more frequently among wild-derived lab strains as well as in ordinary wild mice—if anyone decided to look.
“I’d love to test this hypothesis,” says Omura. “If we picked a wild mouse that’s living on the streets maybe it would have that phenotype–and maybe most lab mice have lost that phenotype.”
In any case, there may be more surprises to be found in CAST/Ei mice. Cox notes that his lab has been studying a mutation that causes a rare childhood motor neuron disease, spinal muscular atrophy with respiratory distress. When bred into the CAST/Ei mice, he says, the disease presentation, or phenotype, becomes significantly milder.
Similarly, Robert W. Burgess, another researcher at the Jackson Laboratory, has found that a genetic condition involving peripheral axon degeneration becomes milder when bred into the CAST/Ei strain.
“It significantly downgrades the phenotype—they are less severe,” Burgess says.
Understanding how that works could be very useful, even if the CAST/Ei resistance to these neurological diseases is due only to a chance genetic variation.
“It’s a pretty powerful strain,” says Burgess.
- See more at: http://dana.org/News/Clue_to_Brain_Regeneration_Discovered_in_Lab_Mice/#sthash.wSYOHCSw.dpuf.
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