Activin Promotes Robust Axonal Regeneration in Brain-Injured Mice

activin-axonIt is well known that axons do not regenerate after injury in the adult central nervous system (CNS) due to a strong growth-inhibitory environment. The intrinsic growth capacity in the brain is thought to be repressed to maintain the stability of synaptic circuitry.

Clifford Woolf of Harvard Medical School [1] led researchers to challenge this long-held dogma, discovering that in fact long-distance axon regeneration in mammals is possible even without genetic manipulation. Specifically, the authors found that neurons in the mammalian CNS can mount a robust regenerative response, and that this effect is mediated by the Activin signal transduction pathway. Activin is a protein complex that plays diverse roles in everything from the immune response to metabolism. Lack of activin during development results in profound intellectual disability. 

Bruce Dobkin of UCLA who was not involved in the study, speculated that activating sprouting with Activin might slow Alzheimer’s disease progression or ALS.

Woolf and colleagues first conducted an inbred mouse neuronal phenotypic screen, finding that a particular CAST/Ei strain extends axons more on CNS myelin than other strains tested. CAST/Ei mice show especially robust regeneration when pre-injured and exhibited the greatest sprouting following ischemic stroke.

The authors reported that: 

These assays revealed that DRG neurons from CAST/Ei mice were capable of producing substantially higher levels of growth on a myelin substrate than all the other strains assayed, measured both as numbers of neurons with neurites and longest axonal process per neuron. The axonal growth in this strain surpassed the average growth of the other strains under naive conditions (2-fold increase, p < 0.01, one-way ANOVA; post hoc Sidak’s, for naive CAST/Ei against all other naive strains) and was markedly greater than the average growth of the other strains after pre-conditioning.

Next, the authors asked whether the growth capacity of injured neurons in the peripheral nervous system of CAST/Ei mice might also translate to enhanced growth in the central nervous system. Zymosan was used to inflict nerve injury and elicit axonal regrowth in two mouse strains, C57BL/6 and CAST/Ei: 

In C57BL/6 animals 6.4 μg and 25 μg of zymosan produced modest and dose-dependent levels of axonal regeneration measured 14 days after the ON injury (Figures 3A and 3B) (Kurimoto et al., 2010 and Yin et al., 2006). The same doses in CAST/Ei mice, however, produced substantially more extensive axonal regeneration, with axons observed as far as 4,000 μm from the crush site reaching close to the optic chiasm.

Woolf et. al. found that CAST/Ei mice exhibit much more robust axonal sprouting than C57BL/6 mice. Moreover, they reported that this phenotype had a high degree of heritability,  suggesting that most inter-strain axonal growth variation can be attributed to genetic factors.

Next, the authors used genome-wide expression profiling to identify candidate genes and pathways that might contribute to the CAST/Ei axonal growth phenotype. Two independent genome-wide screens identified Activin signaling as being most highly correlated with CAST/Ei axonal regeneration. 

Both genetic and pharmacological strategies were employed to interrogate the role of the Activin signaling pathway on axonal regeneration. The authors used both Activin gain of function and loss of function genotypes in the presence of SB-431542, a potent Activin receptor antagonist. They found that SB-431542 markedly reduced neurite initiation and maximal axon length. Conversely exogenous introduction of Activin ligands promoted axonal growth on myelin in C57/B6 mice. 

The authors conclude the following: 

we have found that injured neurons in the mammalian CNS can unexpectedly mount a large regenerative response and show a central role for Activin signaling in mediating this, providing potential therapeutic opportunity for stroke and other forms of traumatic brain injury where injury and a priming inflammation co-exist. Identification of the regenerative potential of injured CNS neurons in the CAST/Ei strain provides an opportunity to begin to exhaustively interrogate molecular mechanisms that may enable CNS regeneration in mammals.

[1] Omura T, Omura K, Tedeschi A, et al. Robust Axonal Regeneration Occurs in the Injured CAST/Ei Mouse CNS. Neuron. 2015;86(5):1215-27.

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