Neuronal differentiation induces SNORD115 expression and is accompanied by post-transcriptional changes of serotonin receptor 2c mRNA

Abstract

The serotonin neurotransmitter system is widespread in the brain and implicated in modulation of neuronal responses to other neurotransmitters. Among 14 serotonin receptor subtypes, 5-HT2cR plays a pivotal role in controlling neuronal network excitability. Serotonergic activity conveyed through receptor 5-HT2cR is regulated post-transcriptionally via two mechanisms, alternative splicing and A-to-I RNA editing. Brain-specific small nucleolar RNA SNORD115 harbours a phylogenetically conserved 18-nucleotide antisense element with perfect complementarity to the region of 5ht2c primary transcript that undergoes post-transcriptional changes. Previous 5ht2c minigene studies have implicated SNORD115 in fine-tuning of both post-transcriptional events. We monitored post-transcriptional changes of endogenous 5ht2c transcripts during neuronal differentiation. Both SNORD115 and 5ht2c were upregulated upon neuronal commitment. We detected increased 5ht2c alternative exon Vb inclusion already at the stage of neuronal progenitors, and more extensive A-to-I editing of non-targeted sites A and B compared to adjacent adenosines at sites E, C and D throughout differentiation. As the extent of editing is known to positively correlate with exon Vb usage while it reduces receptor functionality, our data support the model where SNORD115 directly promotes alternative exon inclusion without the requirement for conversion of key adenosines to inosines, thereby favouring production of full-length receptor isoforms with higher potency.

Whole-transcriptome RNA editing analysis in single cortical neurons links locus 15q11 with psychiatric illness

“…Genomic deletion of the SNORD115 or 116 cluster is sufficient to cause Prader-Willi syndrome (Bieth et al, 2015), which features autistic traits (Descheemaeker et al, 2006). Although SNORD115 RNAs are known to direct editing and splicing of 5HT2C serotonin receptors (Bratkovič et al, 2018), we identified a striking positive association between expression of SNORD115/116 RNAs and editing across the entire transcriptome, which has not been observed previously. This association may have been revealed due to the relative enrichment of nucleolar pre-RNA in this dataset.…”

Small nucleolar RNAs: continuing identification of novel members and increasing diversity of their molecular mechanisms of action

“…Those two functions, which continue to be confirmed by more recent studies (e.g. [56]), are performed simply by masking partially a specific sequence of the mRNA, but have a huge impact on the receptor activity.…”

“…This regulatory mechanism has been extensively described elsewhere (as reviewed for example in [7,55]), but briefly, the orphan SNORD115 was shown to bind the alternative exon Vb of the HTR2C mRNA, the inclusion of which is necessary for functional activity of the resulting receptor. The binding of SNORD115 to the mRNA was shown to serve two main purposes: prevent exonic splicing silencer elements near this region from being bound by splicing regulator proteins and inhibit the A to I base editing of the mRNA [54,[56][57][58]. Those two functions, which continue to be confirmed by more recent studies (e.g.…”

Transcriptional profiling of medulloblastoma with extensive nodularity (MBEN) reveals two clinically relevant tumor subsets with VSNL1 as potent prognostic marker

“…1). These genes encode a small nucleolar RNA pool (non-coding RNAs) which usually functions in guiding the modification of other non-coding RNAs [4]. It has been shown recently that SNORD115 overexpression induces neuronal differentiation [4], and upregulation of these genes could therefore play a role in shaping the neuronal-associated "TCL2 MBEN" variant.…”