Mouse Axons CAST Off Inhibitors for Stunning Regeneration

It is well known that damaged axons from the central nervous system of mammals cannot regrow. Except perhaps they can, with the right genotype. In the May 21 Neuron online, researchers from Boston Children’s Hospital report that a mouse line known as CAST, derived from Asian forebears, possess the capacity for stunning axon regeneration following injury or stroke. Genetic analysis showed this was due in part to their high expression of the signaling protein Activin.

Axon Regeneration: Following optic nerve crush, the axons of standard C57 Black mice make feeble attempts at regrowth (top), while the axons of CAST mice (bottom) forge ahead. [Image courtesy of Neuron, Omura et al.]

While injured neurons in the periphery can sprout anew, those in the central nervous system are stumped by the myelin milieu, which produces factors that block growth (reviewed in Filbin, 2003). Takao Omura, first author on the Neuron paper and a surgeon at the Hamamatsu University School of Medicine in Japan, was frustrated that treatments for CNS injuries have not advanced in decades. He and senior author Clifford Woolf hatched a plan to search for new genes that might help design treatments. They began by comparing genetically different mice to see if some were better at axon regeneration than others. Omura collected nine strains and cultured their dorsal root ganglion neurons on myelin. Most of those neurons extended piddling axons, but the CAST cultures stood out, growing neurites five times longer than the others. “It was amazing,” Omura said. “At first, I thought it was a mistake.”

Omura’s collaborators, in Boston and at the David Geffen School of Medicine at the University of California, Los Angles, tested the CAST mice in classic paradigms of axonal damage—stroke, spinal-cord injury, and optic-nerve crush. In each case, axon regrowth in CAST mice outpaced that of other strains, such as C57 Black. “You see crazy amounts of regeneration,” said Larry Benowitz of Boston Children’s Hospital, whose lab performed the optic nerve experiments (see image above). However, the CAST effect was limited to the CNS; in the periphery, regeneration rates were like those of other mice. The CAST genotype must allow the neurons to ignore the inhibitory signals coming from myelin, reasoned co-senior author Michael Costigan, also at Children’s.

The scientists told Alzforum that CAST mice differ from most mouse lines used in research, which are descended from the “pocket pets” of European mouse fanciers of the Victorian era. The CAST founders were not so dainty—they were wild mice trapped while gorging on grains in a warehouse in Thailand. Costigan’s group profiled the mRNA of the different strains, and determined the CAST mice made unusually large amounts of the gene Activin, a signaling molecule in the TGF-β pathway. Treating CAST dorsal root ganglion neurons with SB-431542, a small molecule inhibitor of the Activin receptor ALK, diminished their neurite growth ability. Adding Activin to C57 Black cultures enhanced axon growth.

Bruce Dobkin of the David Geffen School of Medicine, who was not involved in the study, thought that a pro-Activin treatment might have clinical potential for stroke and spinal-cord injury. He was less optimistic about neurodegenerative diseases, but speculated that activating sprouting might slow Alzheimer’s or ALS. Costigan was also skeptical about treating ALS this way, pointing out that motor neurons project into the periphery, where the CAST genotype made little difference.

Reference:

Omura T, Omura K, Tedeschi A, Riva P, Painter MW, Rojas L, Martin J, Lisi V, Huebner EA, Latremoliere A, Yin Y, Barrett LB, Singh B, Lee S, Crisman T, Gao F, Li S, Kapur K, Geschwind DH, Kosik KS, Coppola G, He Z, Carmichael ST, Benowitz LI, Costigan M, Woolf CJ. Robust Axonal Regeneration Occurs in the Injured CAST/Ei Mouse CNS. Neuron. 2015 May 20; PubMed.


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