MicroRNA-26a supports mammalian axon regeneration in vivo by suppressing GSK3ß expression.

ABSTRACT

MicroRNAs are emerging to be important epigenetic factors that control axon regeneration. Here, we report that microRNA-26a (miR-26a) is a physiological regulator of mammalian axon regeneration in vivo. We demonstrated that endogenous miR-26a acted to target specifically glycogen synthase kinase 3ß (GSK3ß) in adult mouse sensory neurons in vitro and in vivo. Inhibition of endogenous miR-26a in sensory neurons impaired axon regeneration in vitro and in vivo. Moreover, the regulatory effect of miR-26a was mediated by increased expression of GSK3ß because downregulation or pharmacological inhibition of GSK3ß fully rescued axon regeneration. Our results also suggested that the miR-26a-GSK3ß pathway regulated axon regeneration at the neuronal soma by controlling gene expression. We provided biochemical and functional evidences that the regeneration-associated transcription factor Smad1 acted downstream of miR-26a and GSK3ß to control sensory axon regeneration. Our study reveals a novel miR-26a-GSK3ß-Smad1 signaling pathway in the regulation of mammalian axon regeneration. Moreover, we provide the first evidence that, in addition to inhibition of GSK3ß kinase activity, maintaining a lower protein level of GSK3ß in neurons by the microRNA is necessary for efficient axon regeneration.