Gas5 inhibition promotes the axon regeneration in the adult mammalian nervous system

Jul 2, 2022Experimental neurology

Blocking Gas5 helps nerve fibers regrow in the adult mammal nervous system

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Abstract

Gas5 knockout mice display enhanced nerve regeneration ability after sciatic nerve injury.

Long-noncoding RNA Gas5 is identified as a suppressor of axon regeneration.
Gas5 levels are found to be age-dependent, increasing during development and decreasing after nerve injury.
Inhibition of Gas5 expression promotes neurite growth in dorsal root ganglion (DRG) neurons from both mice and rats.
Gas5 overexpression is associated with the inhibition of axon growth in mouse DRG neurons.
Gas5 interacts with soluble Vimentin, which is crucial for peripheral nerve development and regeneration.
Inhibition of Gas5 also enhances optic nerve regeneration, suggesting potential implications for central nervous system repair.

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Neurons in the peripheral nervous system (PNS) have robust regenerative capacity after axon injury, but the regenerative capacity is generally absent in the neurons of the central nervous system (CNS) in mammals. Increasing evidence highlighted the pivotal roles of long-noncoding RNAs (lncRNAs) in development and disease, but the role of LncRNA in triggering the regenerative capacity in CNS and PNS is not well studied. Here, we reported that lncRNA Gas5 is a suppressor for axon regeneration. Bioinformatics analysis shows that Gas5 is age-dependent up-regulated during DRG neurons development and down-regulated after sciatic nerve injury. In vitro, inhibiting the expression of Gas5 promotes the neurite growth of DRG neurons both in mice and rats. Consistently, Gas5 overexpression inhibits axon growth of mice DRG neurons. In vivo, Gas5 knockout(Gas5-/-) mice display enhanced nerve regeneration ability after sciatic nerve injury. RNA pull-down analysis indicates that Gas5 can interacts with soluble Vimentin, which is essential for peripheral nerve development and regeneration. Vimentin knockdown reverses the Gas5 silence-regulated axon pro-regeneration demonstrating that the function of Gas5 depending on Vimentin. Besides, inhibition of Gas5 expression can also enhance optic nerve regeneration indicating a potential pro-regenerative ability of Gas5 silence in CNS. Our study for the first time provides direct evidence in vivo that lncRNA plays a role in regulating central axon regrowth and Gas5 might be a novel therapeutic target for axon regeneration in both PNS and CNS.

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Gas5 inhibition promotes the axon regeneration in the adult mammalian nervous system

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