MiR-129 controls axonal regeneration via regulating insulin-like growth factor-1 in peripheral nerve injury

Hui Zhu,Hongkui Wang,Yongjun Wang,Bin Yu,Shiying Li,Min Yao,Chengbin Xue,Xiaosong Gu,Songlin Zhou,Tianmei Qian,Ping Zhang

doi:10.1038/s41419-018-0760-1

Abstract

The microenvironment of peripheral nerve regeneration consists of multiple neurotrophic factors, adhesion molecules, and extracellular matrix molecules, secreted by unique glial cells in the peripheral nerve system (PNS)-Schwann cell (SCs). Following peripheral nerve injury (PNI), local IGF-1 production is upregulated in SCs and denervated muscle during axonal sprouting and regeneration. Regulation of IGF-1/IGF-1R signaling is considered as a potentially targeted therapy of PNI. We previously identified a group of novel miRNAs in proximal nerve following rat sciatic nerve transection. The present work focused on the role of miR-129 in regulation of IGF-1 signaling after sciatic nerve injury. The temporal change profile of the miR-129 expression was negatively correlated with the IGF-1 expression in proximal nerve stump and dorsal root ganglion (DRG) following sciatic nerve transection. An increased expression of miR-129 inhibited proliferation and migration of SCs, and axonal outgrowth of DRG neurons, which was inversely promoted by silencing of the miR-129 expression. The IGF-1 was identified as one of the multiple target genes of miR-129, which exerted negative regulation of IGF-1 by translational suppression. Moreover, knockdown of IGF-1 attenuated the promoting effects of miR-129 inhibitor on proliferation and migration of SCs, and neurite outgrowth of DRG neurons. Overall, our data indicated that miR-129 own the potential to regulate the proliferation and migration of SCs by targeting IGF-1, providing further insight into the regulatory role of miRNAs in peripheral nerve regeneration. The present work not only provides new insight into miR-129 regulation of peripheral nerve regeneration by robust phenotypic modulation of neural cells, but also opens a novel therapeutic window for PNI by mediating IGF-1 production. Our results may provide further experimental basis for translation of the molecular therapy into the clinic.

Highlights

Axonal regeneration depends on the intrinsic growth capacity of neurons and the reaction of glial cells, which expresses proteins that inhibit or promote axonal regeneration[1]
The results showed that insulin-like growth factors (IGFs)-1 expressed in dorsal root ganglion (DRG) neurons and Schwann cells (SCs) of the sciatic nerve (Fig. 1a,b)
Insulin-like growth factor 1 (IGF-1) was showed up-regulated in DRGs and SCs of the proximal nerve segment at 7 days following sciatic nerve injury

Summary

Introduction

Axonal regeneration depends on the intrinsic growth capacity of neurons and the reaction of glial cells, which expresses proteins that inhibit or promote axonal regeneration[1]. Peripheral nerve injury (PNI) initiates a sequential response known as Wallerian degeneration, characterized by axonal degeneration and dedifferentiation of Schwann cells (SCs)[2], which secrete trophic factors and provide the Büngner’s bands guiding axonal growth[3]. The microenvironment of peripheral nerve regeneration consists of multiple neurotrophic factors, adhesion molecules, and extracellular matrix molecules, secreted by multiple cells including SCs in the peripheral nerve system (PNS). The increased expression of insulin-like growth factors (IGFs) in the injured nerve has been suggested to facilitate axonal regeneration after PNI9. Insulin-like growth factor 1 (IGF-1) is a polypeptide hormone with critical roles in peripheral nerve regeneration. Rab8a regulates IGF-1 secretion in a GDP-bound form dependent manner[17]

Methods

Results

Conclusion