Abstract
Serotonin 5-HT2C receptor is a G-protein coupled excitatory receptor that regulates several biochemical pathways and has been implicated in obesity, mental state, sleep cycles, autism, neuropsychiatric disorders and neurodegenerative diseases. The activity of 5-HT2CR is regulated via alternative splicing and A to I editing of exon Vb of its pre-mRNA. Snord115 is a small nucleolar RNA that is expressed in mouse neurons and displays an 18-nucleotide base complementary to exon Vb of 5-HT2CR pre-mRNA. For almost two decades this putative guide element of Snord115 has wandered like a ghost through the literature in attempts to elucidate the biological significance of this complementarity. In mice, Snord115 is expressed in neurons and absent in the choroid plexus where, in contrast, 5-Ht2cr mRNA is highly abundant. Here we report the analysis of 5-Ht2cr pre-mRNA posttranscriptional processing via RNA deep sequencing in a mouse model that ectopically expresses Snord115 in the choroid plexus. In contrast to previous reports, our analysis demonstrated that Snord115 does not control alternative splicing of 5-Ht2cr pre-mRNA in vivo. We identified a modest, yet statistically significant reduction of 5-Ht2cr pre-mRNA A to I editing at the major A, B, C and D sites. We suggest that Snord115 and exon Vb of 5Ht2cr pre-mRNA form a double-stranded structure that is subject to ADAR-mediated A to I editing. To the best of our knowledge, this is the first comprehensive Snord115 gain-of-function analysis based on in vivo mouse models.
Highlights
The 5-hydroxytryptamine receptor 2C (5-HT2CR) belongs to the superfamily of G-protein coupled receptors and interacts with its endogenous ligand, the neurotransmitter serotonin (5-hydroxytryptamine, 5-HT). 5-HT2C receptor signaling regulates a wide variety of biochemical circuits, which among others, have been implicated in obesity, appetite, mental state, sleep cycles, autism, neuropsychiatric disorders and neurodegenerative diseases (e.g., Parkinson, Alzheimer)[1,2,3,4]
With RNA high throughput sequencing, we analyzed the patterns of 5-Ht2cr pre-mRNA posttranscriptional processing in PWScrp−/m5′LoxP and wild type mice
RNomics discovered a number of small nucleolar RNAs (snoRNAs) that direct site-specific 2′-O-methylation or pseudouridylation of ribosomal RNAs (rRNAs) and snRNAs targets, but could possibly be involved in other cellular processes including those that underlie human diseases[10,35,36,37]
Summary
The 5-hydroxytryptamine receptor 2C (5-HT2CR) belongs to the superfamily of G-protein coupled receptors and interacts with its endogenous ligand, the neurotransmitter serotonin (5-hydroxytryptamine, 5-HT). 5-HT2C receptor signaling regulates a wide variety of biochemical circuits, which among others, have been implicated in obesity, appetite, mental state, sleep cycles, autism, neuropsychiatric disorders (e.g., schizophrenia, depression) and neurodegenerative diseases (e.g., Parkinson, Alzheimer)[1,2,3,4]. The efficiency of 5-HT2CR G-protein coupling is regulated by posttranscriptional A to I editing within the CDS (coding sequence) of the second internal loop of the receptor[7,8,9]. Acting on RNA) enzymes catalyze receptor pre-mRNA (precursor mRNA) editing at five different sites: ADAR1: A, B, C and E – sites and ADAR2: C, D and E sites, respectively[10,11,12,13]. Combinations of these individual editing events amount to 32 different 5-HT2CR mRNA isoforms, which collectively modulate the serotonergic signal transduction to varying degrees[14,15]. No significant base complementarities with “classical” snoRNA targets such as ribosomal RNAs (rRNAs) have been established; they are categorized as “orphan” snoRNA with potentially non-canonical functions[16,17]
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