Addition of a carboxy terminal tail to the normally tailless gonadotropin-releasing hormone receptor impairs fertility in female mice

  1. Chirine Toufaily
  2. Jérôme Fortin
  3. Carlos AI Alonso
  4. Evelyne Lapointe
  5. Xiang Zhou
  6. Yorgui Santiago-Andres
  7. Yeu-Farn Lin
  8. Yiming Cui
  9. Ying Wang
  10. Dominic Devost
  11. Ferdinand Roelfsema
  12. Frederik Steyn
  13. Aylin C Hanyaloglu
  14. Terence E Hébert
  15. Tatiana Fiordelisio
  16. Derek Boerboom
  17. Daniel J Bernard  Is a corresponding author
  1. McGill University, Canada
  2. Universite de Montreal, Canada
  3. Universidad Nacional Autónoma de México, Mexico
  4. Leiden University Medical Center, Netherlands
  5. The University of Queensland, Australia
  6. Imperial College London, United Kingdom

Abstract

Gonadotropin-releasing hormone (GnRH) is the primary neuropeptide controlling reproduction in vertebrates. GnRH stimulates follicle-stimulating hormone (FSH) and luteinizing hormone (LH) synthesis via a G protein-coupled receptor, GnRHR, in the pituitary gland. In mammals, GnRHR lacks a C-terminal cytosolic tail (Ctail) and does not exhibit homologous desensitization. This might be an evolutionary adaptation that enables LH surge generation and ovulation. To test this idea, we fused the chicken GnRHR Ctail to the endogenous murine GnRHR in a transgenic model. The LH surge was blunted, but not blocked in these mice. In contrast, they showed reductions in FSH production, ovarian follicle development, and fertility. Addition of the Ctail altered the nature of agonist-induced calcium signaling required for normal FSH production. The loss of the GnRHR Ctail during mammalian evolution is unlikely to have conferred a selective advantage by enabling the LH surge. The adaptive significance of this specialization remains to be determined.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Chirine Toufaily

    Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  2. Jérôme Fortin

    Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  3. Carlos AI Alonso

    Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  4. Evelyne Lapointe

    Département de biomédecine vétérinaire, Universite de Montreal, Ste-Hyacinthe, Canada
    Competing interests
    The authors declare that no competing interests exist.
  5. Xiang Zhou

    Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  6. Yorgui Santiago-Andres

    Departamento de Ecología y Recursos Naturales, Universidad Nacional Autónoma de México, Mexico City, Mexico
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7343-7746
  7. Yeu-Farn Lin

    Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  8. Yiming Cui

    Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  9. Ying Wang

    Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  10. Dominic Devost

    Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  11. Ferdinand Roelfsema

    Department of Internal Medicine, Leiden University Medical Center, Leiden, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  12. Frederik Steyn

    School of Biomedical Sciences, The University of Queensland, Brisbane, Australia
    Competing interests
    The authors declare that no competing interests exist.
  13. Aylin C Hanyaloglu

    Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4206-737X
  14. Terence E Hébert

    Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  15. Tatiana Fiordelisio

    3epartamento de Ecología y Recursos Naturales, Universidad Nacional Autónoma de México, Mexico City, Mexico
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9282-1476
  16. Derek Boerboom

    Département de biomédecine vétérinaire, Universite de Montreal, Ste-Hyacinthe, Canada
    Competing interests
    The authors declare that no competing interests exist.
  17. Daniel J Bernard

    Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada
    For correspondence
    daniel.bernard@mcgill.ca
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5365-5586

Funding

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

Ethics

Animal experimentation: All mouse experiments in Canada were performed in accordance with institutional and federal guidelines and were approved by the McGill University Facility Animal Care Committee (DOW-A; protocol 5204). Mouse studies conducted at the National University of Mexico were performed under an institutional protocol similar to the United States Public Health Service Guide for the Care and Use of Laboratory Animals, and according to the Official Mexican Guide from the Secretary of Agriculture (SAGARPA NOM-062-Z00-1999).

Reviewing Editor

  1. Rajan Dighe, Indian Institute of Science Bangalore, India

Publication history

  1. Received: August 10, 2021
  2. Preprint posted: September 16, 2021 (view preprint)
  3. Accepted: December 6, 2021
  4. Accepted Manuscript published: December 23, 2021 (version 1)
  5. Version of Record published: January 7, 2022 (version 2)

Copyright

© 2021, Toufaily 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. Chirine Toufaily
  2. Jérôme Fortin
  3. Carlos AI Alonso
  4. Evelyne Lapointe
  5. Xiang Zhou
  6. Yorgui Santiago-Andres
  7. Yeu-Farn Lin
  8. Yiming Cui
  9. Ying Wang
  10. Dominic Devost
  11. Ferdinand Roelfsema
  12. Frederik Steyn
  13. Aylin C Hanyaloglu
  14. Terence E Hébert
  15. Tatiana Fiordelisio
  16. Derek Boerboom
  17. Daniel J Bernard
(2021)
Addition of a carboxy terminal tail to the normally tailless gonadotropin-releasing hormone receptor impairs fertility in female mice
eLife 10:e72937.
https://doi.org/10.7554/eLife.72937

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