MiR-340 Regulates Fibrinolysis and Axon Regrowth Following Sciatic Nerve Injury

Abstract

After peripheral nerve injury, the degenerative debris and inflammatory alterations at the injury site may block the elongation of regenerating axons to reach target organs. Tissue plasminogen activator (tPA), a serine protease, has a capability of degrading matrix molecules and cell adhesions. In this study, we found that either tPA or miR-340 was differentially expressed in the injured nerve after sciatic nerve injury, and that the expressions of tPA and miR-340 were negatively correlated to each other. Moreover, miR-340 and tPA were co-localized in sciatic nerve. miR-340 regulated tPA through direct targeting of the 3'-UTR of tPA. Functionally, over- or under-expression of miR-340 reduced or augmented the fibrinolytic activity and migration ability of cultured Schwann cells as well as tPA secretion from the cells, respectively. In rats with sciatic nerve crush injury, dysregulation of the miR-340 expression in the injury site affected the cell debris removal and axonal regrowth. Obviously, unlike many previous studies that investigate the functional impact of miRNAs on peripheral nerve regeneration in the perspective of miRNA regulation of neural cell behaviors, the present study focused on miRNA regulation of debris clearance, thus updating our understanding of the regulatory roles of miRNAs in peripheral nerve regeneration.

The microRNAs let-7 and miR-9 down-regulate the axon-guidance genes Ntn1 and Dcc during peripheral nerve regeneration

“…Our previous studies showed that after sciatic nerve injury, let-7 and miR-1 regulate the phenotype of SCs by directly targeting the nerve growth factors, NGF and BDNF separately, and further promoting the axon growth of sciatic nerve (12,13). In addition, we found that miR-340 could target and regulate the tPA for debris clearance and axon growth (14). In the current study, we explored the regulation mechanism of axon guidance during peripheral nerve regeneration.…”

“…In animals, miRNAs bind to partially complementary sites in mRNAs, leading to translational repression and mRNA deadenylation and degradation (8 -10). Previously, we identified a series of differentially expressed miRNAs and found that these miRNAs affect the microenvironment after peripheral nerve regeneration (11)(12)(13)(14)(15). Debris removal, axonal growth, and axon guidance are key elements that affect the regenerative microenvironment and contribute to peripheral nerve regeneration.…”

Large‐scale identification of functional microRNA targeting reveals cooperative regulation of the hemostatic system

“…In contrast, the F11/miR‐181a interaction was identified in the miTRAP assay in addition to F11/miR‐181b, a member of the same seed‐family; however, only F11/miR‐181b functionality was confirmed by miRNA‐mimic‐rescue. PLAT/miR‐340 showed a significant enrichment in the miTRAP assay of 4.7‐fold. However, as this was below the cut‐off of 5‐fold enrichment, this interaction was not selected for validation with miRNA‐mimic‐rescue.…”

Noncoding RNAs and Their Potential Therapeutic Applications in Tissue Engineering

“…miR-340 regulates fibrinolysis, and also influences debris removal and axonal regrowth during sciatic nerve regeneration by targeting tPA, a serine protease with the capability of degrading matrix molecules and cell adhesions [62].…”