Re-assessment 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.

Data availability

RiboMeth-seq data are available on GEO under the accession number GSE145159Raw data (mRNAseq) are available on Sequence Read Archive (SRA) database under the accession number PRJNA608249.Raw data (A-to-I RNA editing) are available on Sequence Read Archive (SRA) database under the accession numbers PRJNA603261 and PRJNA603264. Scripts used for that analysis, detailed instructions and intermediary data have been deposited at https://github.com/HKeyHKey/Hebras_et_al_2020

The following data sets were generated

Article and author information

Author details

  1. Jade Hebras

    LBME, CNRS, Toulouse, France
    Competing interests
    The authors declare that no competing interests exist.
  2. Virginie Marty

    LBME, CNRS, Toulouse, France
    Competing interests
    The authors declare that no competing interests exist.
  3. Jean Personnaz

    I2MC-U1048, Inserm, Toulouse, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6447-780X
  4. Pascale Mercier

    IPBS-UMR5089, CNRS, Toulouse, France
    Competing interests
    The authors declare that no competing interests exist.
  5. Nicolai Krogh

    Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark
    Competing interests
    The authors declare that no competing interests exist.
  6. Henrik Nielsen

    Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark
    Competing interests
    The authors declare that no competing interests exist.
  7. Marion Aguirrebengoa

    BigA facility, CBI, UPS, CNRS, Toulouse, France
    Competing interests
    The authors declare that no competing interests exist.
  8. Hervé Seitz

    IGH, CNRS, Montpellier, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8172-5393
  9. Jean-Phillipe Pradere

    I2MC-U1048, Inserm, Toulouse, France
    Competing interests
    The authors declare that no competing interests exist.
  10. Bruno P Guiard

    CRCA, CNRS, Toulouse, France
    Competing interests
    The authors declare that no competing interests exist.
  11. Jérôme Cavaille

    LBME, CNRS, Toulouse, France
    For correspondence
    jerome.cavaille@univ-tlse3.fr
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2833-6836

Funding

Fundation for Prader-Willi research

  • Jérôme Cavaille

Fondation pour la Recherche Médicale (DEQ20160334936)

  • Jérôme Cavaille

Agence Nationale de la Recherche (ANR-18-CE12-0008-01)

  • Jérôme Cavaille

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Thomas R Gingeras, Cold Spring Harbor Laboratory, United States

Ethics

Animal experimentation: Animal procedures were approved by the University of Toulouse and CNRS Institutional Animal Care Committee (DAP2016061716367988 and DAP2018011214542827). The animal housing facility met CNRS standards

Version history

  1. Received: August 17, 2020
  2. Accepted: September 22, 2020
  3. Accepted Manuscript published: October 5, 2020 (version 1)
  4. Version of Record published: November 18, 2020 (version 2)

Copyright

© 2020, Hebras et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Jade Hebras
  2. Virginie Marty
  3. Jean Personnaz
  4. Pascale Mercier
  5. Nicolai Krogh
  6. Henrik Nielsen
  7. Marion Aguirrebengoa
  8. Hervé Seitz
  9. Jean-Phillipe Pradere
  10. Bruno P Guiard
  11. Jérôme Cavaille
(2020)
Re-assessment of the involvement of Snord115 in the serotonin 2C receptor pathway in a genetically relevant mouse model
eLife 9:e60862.
https://doi.org/10.7554/eLife.60862

Share this article

https://doi.org/10.7554/eLife.60862

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