LncRNA Rik-203 contributes to anesthesia neurotoxicity via microRNA-101a-3p and GSK-3β-mediated neural differentiation

Abstract

The mechanism of anesthesia neurotoxicity remains largely to be determined. The effects of long noncoding RNAs (LncRNAs) on neural differentiation and the underlying mechanisms are unknown. We thus identified LncRNA Rik-203 (C130071C03Rik) and studied its role on neural differentiation and its interactions with anesthetic sevoflurane, miRNA and GSK-3β. We found that levels of Rik-203 were higher in hippocampus than other tissues and increased during neural differentiation. Sevoflurane decreased the levels of Rik-203. Rik-203 knockdown reduced mRNA levels of Sox1 and Nestin, the markers of neural progenitor cells, and decreased the count of Sox1 positive cells. RNA-RNA pull-down showed that miR-101a-3p was highly bound to Rik-203. Finally, sevoflurane, knockdown of Rik-203, and miR-101a-3p overexpression all decreased GSK-3β levels. These data suggest that Rik-203 facilitates neural differentiation by inhibiting miR-101a-3p’s ability to reduce GSK-3β levels and that LncRNAs would serve as the mechanism of the anesthesia neurotoxicity.

Dissecting the Effect of a 3D Microscaffold on the Transcriptome of Neural Stem Cells with Computational Approaches: A Focus on Mechanotransduction

“…In particular, we found five downregulated lincRNAs (2900076A07Rik, Gm16892, Gm4262, Gm807, and C130071C03Rik) associated to pluripotency. Specifically, 2900076A07Rik, Gm16892, Gm4262, and Gm807 activation has been correlated to reprogramming of mouse fibroblasts [37], while C130071C03Rik facilitates neuronal differentiation sponging miR-101a-3p in mouse hippocampal tissue [38].…”

LncRNA Rik-203 Contributes to Sevoflurane Induced Neurotoxicity?

“…In our previous study, we found that LncRNA Rik-203 contributes to anesthesia induced inhibition of neural differentiation (26). Rik-203 expression level was significantly lower in the hippocampus of mice exposed with 3% sevoflurane 2 h daily for 3 days (Figure 1A).…”

“…Specifically, the cells were treated with 4.1% sevoflurane for 2 h daily at day 4, 5, and 6 after the start of neural differentiation to mimic the clinical several times anesthesia. The cells were harvested at day 7 during the neural differentiation, at which there're many NPCs (26). In some experiments, the cells were transfected with BDNF 12 h before the sevoflurane treatment.…”

“…LncRNA Rik-201 plays important role in gliomagenesis (31). In our previous study, LncRNA Rik-203 contributes to anesthesia induced neurotoxicity by regulating neural differentiation (26). Moreover, LncRNA Rik-201 and LncRNA Rik-203 attached to microRNAs (miRNAs) as a sponge to prevent the miRNA from binding to mRNA 3 ′ UTR, thus inhibiting miRNA's ability to bind to target mRNA and prevent the translation to regulate neural differentiation (32).…”

The functions of long non-coding RNAs in neural stem cell proliferation and differentiation

“…Suppression of Rik-201 and Rik-203 restrained neural differentiation via acting as ceRNAs of miR-96 and miR-467a-3p, respectively, which deinhibition restricted the expression of neural differentiation-related gene Sox6 [64]. Sevoflurane was also reported to attenuating the expression of lncRNA Rik-203 that resulted in the release of miR-101-3a but lessening Glycogen Synthase Kinase-3β (GSK-3β) level, ultimately inhibited neural differentiation [65]. Furthermore, miR-128-3p is abundantly expressed in brain and emerges as a key modulator in neural differentiation, which overexpression prohibited neuron but enhanced gliocytes differentiation.…”