Involvement of the miR-363-5p/P2RX4 Axis in Regulating Schwann Cell Phenotype after Nerve Injury

Abstract

Although microRNAs (miRNAs or miRs) have been studied in the peripheral nervous system, their function in Schwann cells remains elusive. In this study, we performed a microRNA array analysis of cyclic adenosine monophosphate (cAMP)-induced differentiated primary Schwann cells. KEGG pathway enrichment analysis of the target genes showed that upregulated miRNAs (mR212-5p, miR335, miR20b-5p, miR146b-3p, and miR363-5p) were related to the calcium signaling pathway, regulation of actin cytoskeleton, retrograde endocannabinoid signaling, and central carbon metabolism in cancer. Several key factors, such as purinergic receptors (P2X), guanine nucleotide-binding protein G(olf) subunit alpha (GNAL), P2RX5, P2RX3, platelet-derived growth factor receptor alpha (PDGFRA), and inositol 1,4,5-trisphosphate receptor type 2 (ITPR2; calcium signaling pathway) are potential targets of miRNAs regulating cAMP. Our analysis revealed that miRNAs were differentially expressed in cAMP-treated Schwann cells; miRNA363-5p was upregulated and directly targeted the P2X purinoceptor 4 (P2RX4)-UTR, reducing the luciferase activity of P2RX4. The expression of miRNA363-5p was inhibited and the expression of P2RX4 was upregulated in sciatic nerve injury. In contrast, miRNA363-5p expression was upregulated and P2RX4 expression was downregulated during postnatal development. Of note, a P2RX4 antagonist counteracted myelin degradation after nerve injury and increased pERK and c-Jun expression. Interestingly, a P2RX4 antagonist increased the levels of miRNA363-5p. This study suggests that a double-negative feedback loop between miRNA363-5p and P2RX4 contributes to the dedifferentiation and migration of Schwann cells after nerve injury.

Tissue‐engineered in vitro modeling of the impact of Schwann cells in amyotrophic lateral sclerosis

“…Exosomes or micro-RNAs released by Schwann cells can also participate in the modulation of axonal migration (J. Chen et al, 2019;Ching et al, 2018;Sohn et al, 2021). The alteration of one or more of these mechanisms induced by the mutant SOD1 overexpression in Schwann cells may explain their decreased ability to promote MN axonal migration.…”

A Double-Negative Feedback Interaction between miR-21 and PPAR-α in Clear Renal Cell Carcinoma

“…Previous studies have shown that transcriptional regulation mediated by transcription factors and the post-transcriptional control exerted by miRNAs are often highly coordinated [41][42][43]. In particular, the interplay between miRNAs and transcriptional regulators has been shown to regulate key developmental events or cell-fate decisions [41][42][43]. In particular, one well-described network motif, the double-negative feedback loop, is thought to regulate many binary cell-fate decisions [42][43][44].…”

“…In particular, the interplay between miRNAs and transcriptional regulators has been shown to regulate key developmental events or cell-fate decisions [41][42][43]. In particular, one well-described network motif, the double-negative feedback loop, is thought to regulate many binary cell-fate decisions [42][43][44]. This regulatory mechanism implies that one miRNA targets a transcriptional regulator, which in turn controls the expression of this miRNA and usually acts as a switch between two alternative cell states [42][43][44][45].…”

“…In particular, one well-described network motif, the double-negative feedback loop, is thought to regulate many binary cell-fate decisions [42][43][44]. This regulatory mechanism implies that one miRNA targets a transcriptional regulator, which in turn controls the expression of this miRNA and usually acts as a switch between two alternative cell states [42][43][44][45]. In this study, we propose that, in ccRCC, miR-21 and PPAR-α function in a double-negative feedback loop, where miR-21 and PPAR-α mutually repress each other to control lipid metabolism (Figure 7).…”

MicroRNA: Crucial modulator in purinergic signalling involved diseases

“…Interestingly, a P2X4 receptor antagonist increased the levels of miR-363-5p. In brief, the correlation between miR-363-5p and the P2X4 receptor contributes to the dedifferentiation and migration of Schwann cells after nerve injury [64]. In spinal cord injury (SCI), blockage of P2X7 receptors and other purinergic receptors provides neuroprotection in rats [65][66][67].…”