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 3β (GSK3β) 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 GSK3β because downregulation or pharmacological inhibition of GSK3β fully rescued axon regeneration. Our results also suggested that the miR-26a-GSK3β 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 GSK3β to control sensory axon regeneration. Our study reveals a novel miR-26a-GSK3β-Smad1 signaling pathway in the regulation of mammalian axon regeneration. Moreover, we provide the first evidence that, in addition to inhibition of GSK3β kinase activity, maintaining a lower protein level of GSK3β in neurons by the microRNA is necessary for efficient axon regeneration.
Highlights
Epigenetic regulation independent of changes to DNA sequences is emerging to be a key cellular mechanism to control gene expression, in particular in proliferating cells, such as cancer and stem cells
We found that the level of GSK3β, but not GSK3α, was significantly increased (Figures 1a–c) upon Dicer knockdown, indicating that GSK3β in sensory neurons is regulated by the microRNAs
To identify the specific microRNA targeting GSK3β, we used a neuronal cell line to test the regulatory effects of several potential candidates based on the 3′-untranslated region (3′-UTR) sequence of GSK3β and previous studies, including microRNA-23b, microRNA-28a, microRNA-221, microRNA-135b, microRNA-101a, microRNA-26a and microRNA-603
Summary
Epigenetic regulation independent of changes to DNA sequences is emerging to be a key cellular mechanism to control gene expression, in particular in proliferating cells, such as cancer and stem cells. Our recent study[8] has provided the first in vivo evidence that microRNA-138 and its target histone deacetylase SIRT1 have important roles in the regulation of gene expression during mammalian axon regeneration in vivo. Many previous studies, including ours, have shown that glycogen synthase kinase 3 (GSK3) signaling has very important roles in the regulation of axon regeneration. We have shown that moderate inactivation of GSK3 at the nerve growth cone is necessary for efficient axon regeneration by promoting microtubule stability.[9] In addition, our recent study has revealed that localized inactivation of GSK3 at the neuronal soma is required for axon regeneration by controlling nerve injury-induced gene expression.[10] either pharmacological inhibition of GSK311 or conditionally knocking out GSK3β12 is able to promote axon regeneration in the spinal cord. We have revealed a new regulatory mechanism of GSK3 signaling: a lower level of GSK3 protein needs to be maintained by microRNAs in neurons to support efficient axon regeneration
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