Reassessment of the involvement of Snord115 in the serotonin 2c receptor pathway in a genetically relevant mouse model

Abstract

SNORD115 has been proposed to promote the activity of serotonin (HTR2C) receptor via its ability to base-pair with its pre-mRNA and regulate alternative RNA splicing and/or A-to-I RNA editing. Because SNORD115 genes are deleted in most patients with the Prader-Willi syndrome (PWS), diminished HTR2C receptor activity could contribute to the impaired emotional response and/or compulsive overeating characteristic of this disease. In order to test this appealing but never demonstrated hypothesis in vivo, we created a CRISPR/Cas9-mediated Snord115 knockout mouse. Surprisingly, we uncovered only modest region-specific alterations in Htr2c RNA editing profiles while Htr2c alternative RNA splicing was unchanged. These subtle changes, whose functional relevance remains uncertain, were not accompanied by any discernible defects in anxio-depressive-like phenotypes. Energy balance and eating behaviour were also normal, even after exposure to high fat diet. Our study raises questions concerning the physiological role of SNORD115, notably its involvement in behavioural disturbance associated with PWS.

Animal Models of Depression: What Can They Teach Us about the Human Disease?

“…The use of Cre-driver mouse lines for targeting local specific brain areas associated with depression and emotionality such as forebrain, hippocampus and VTA, provides a new approach to investigate proof of concept as to how the brain modulates mood and mood disorders [ 311 , 312 ]. Within the development of Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-associated protein 9 (Cas9) system (CRISPR/Cas9) technology, the new generation of KO mice were developed in order to investigate the role of specific proteins on depression-like phenotype development and for further translation to clinical depression [ 313 , 314 , 315 ].…”

A Comprehensive Review of Genetically Engineered Mouse Models for Prader-Willi Syndrome Research

“…RNA deep sequencing analysis of choroid plexus samples from a mouse model with ectopic Snord115 expression revealed that Snord115 is not involved in the regulation of 5-Ht2cr pre-mRNA alternative splicing in vivo [ 139 ]. Recently, a long-awaited mouse model harboring the paternal deletion of the Snord115 gene cluster in the C57BL/6J genetic background was reported ( Figure 1 C,D; Table 1 ) [ 44 ]. RNA deep sequencing of different brain areas revealed that the lack of Snord115 expression does not alter alternative splicing of 5-Ht2cr pre-mRNA [ 44 ].…”

“…Recently, a long-awaited mouse model harboring the paternal deletion of the Snord115 gene cluster in the C57BL/6J genetic background was reported ( Figure 1 C,D; Table 1 ) [ 44 ]. RNA deep sequencing of different brain areas revealed that the lack of Snord115 expression does not alter alternative splicing of 5-Ht2cr pre-mRNA [ 44 ]. Likewise, transcriptome analysis of hypothalamus samples from PWS patients did not detect differences in 5-HT2CR pre-mRNA splicing [ 140 ].…”

“…Consequently, analysis of 5-Ht2cr pre-mRNA revealed only a modestly reduced A-to-I editing at major sites, questioning the overall biological significance of the Snord115-5Ht2c receptor pre-mRNA interaction and its contribution to PWS pathophysiology [ 139 ]. A mouse model with a paternal deletion of the Snord115 gene cluster also revealed only modest alterations in 5-Htr2cr mRNA editing profiles [ 44 ]; moreover, differences were detected in a brain region-specific manner. The functional significance of these minor changes remains to be resolved, as mice showed no obvious phenotypic abnormalities, they bred normally, displayed normal growth patterns and energy balance on either a normal chow or high fat diet.…”

Pharmacodynamic Gene Testing in Prader-Willi Syndrome

“…There are epigenetic effects on the editing of serotonin 2C receptor believed to be caused by base pair complementarity with one of the sno-RNAs in the critical region, specifically SNORD115 (Kishore and Stamm, 2006). However, the loss of SNORD115 in animal models does not appear to be sufficient to cause the abnormal editing of HTR2C (Hebras et al, 2020). Falaleeva et al (2015) has proposed a mutual interaction between SNORDs, where SNORD116 is necessary to facilitate alternative splicing of RNAs by SNORD115, and SNORD115 modulates the expression of genes by SNORD116, although none of those appear to be directly related to the pharmacodynamic genes in this case report (Falaleeva et al, 2015).…”