1. Neuroscience

Phox2b mutation mediated by Atoh1 expression impaired respiratory rhythm and ventilatory responses to hypoxia and hypercapnia

  1. Caroline B Ferreira
  2. Talita M Silva
  3. Phelipe E Silva
  4. Claudio L Castro
  5. Catherine Czeisler
  6. José J Otero
  7. Ana C Takakura  Is a corresponding author
  8. Thiago S Moreira  Is a corresponding author
  1. University of São Paulo, Brazil
  2. The Ohio State University, United States
https://doi.org/10.7554/eLife.73130
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Cite this article
  1. Caroline B Ferreira
  2. Talita M Silva
  3. Phelipe E Silva
  4. Claudio L Castro
  5. Catherine Czeisler
  6. José J Otero
  7. Ana C Takakura
  8. Thiago S Moreira
(2022)
Phox2b mutation mediated by Atoh1 expression impaired respiratory rhythm and ventilatory responses to hypoxia and hypercapnia
eLife 11:e73130.
https://doi.org/10.7554/eLife.73130
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Abstract

Mutations in the transcription factor Phox2b cause congenital central hypoventilation syndrome (CCHS). The syndrome is characterized by hypoventilation and inability to regulate breathing to maintain adequate O2 and CO2 levels. The mechanism by which CCHS impact respiratory control are incompletely understood, and even less is known about the impact of the non-polyalanine repeat expansion mutations (NPARM) form. Our goal was to investigate the extent by which NPARM Phox2b mutation affect a) respiratory rhythm; b) ventilatory responses to hypercapnia (HCVR) and hypoxia (HVR) and c) number of chemosensitive neurons in mice. We used a transgenic mouse line carrying a conditional Phox2bΔ8 mutation (same found in humans with NPARM CCHS). We crossed them with Atoh1cre mice to introduce mutation in regions involved with respiratory function and central chemoreflex control. Ventilation was measured by plethysmograph during neonatal and adult life. In room air, mutation in neonates and adult did not greatly impact basal ventilation. However, Phox2bΔ8, Atoh1cre increased breath irregularity in adults. The HVR and HCVR were impaired in neonates. The HVR, but not HCVR was still partially compromised in adults. The mutation reduced the number of Phox2b+/TH- expressing neurons as well as the number of fos-activated cells within the ventral parafacial region (also named retrotrapezoid region - RTN) induced by hypercapnia. Our data indicates that Phox2bΔ8 mutation in Atoh1-expressing cells impaired RTN neurons, as well as chemoreflex under hypoxia and hypercapnia specially early in life. This study provided new evidence for mechanisms related to NPARM form of CCHS neuropathology.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting file; Source Data files have been provided for Figures 1-6.

Article and author information

Author details

  1. Caroline B Ferreira

    Department of Pharmacology, University of São Paulo, São Paulo, Brazil
    Competing interests
    The authors declare that no competing interests exist.

  2. Talita M Silva

    Department of Physiology and Biophysics, University of São Paulo, São Paulo, Brazil
    Competing interests
    The authors declare that no competing interests exist.

  3. Phelipe E Silva

    Department of Physiology and Biophysics, University of São Paulo, São Paulo, Brazil
    Competing interests
    The authors declare that no competing interests exist.

  4. Claudio L Castro

    Department of Physiology and Biophysics, University of São Paulo, São Paulo, Brazil
    Competing interests
    The authors declare that no competing interests exist.

  5. Catherine Czeisler

    Department of Pathology, The Ohio State University, Columbus, United States
    Competing interests
    The authors declare that no competing interests exist.

  6. José J Otero

    Department of Pathology, The Ohio State University, Columbus, United States
    Competing interests
    The authors declare that no competing interests exist.

  7. Ana C Takakura

    Department of Pharmacology, University of São Paulo, São Paulo, Brazil
    For correspondence
    takakura@icb.usp.br
    Competing interests
    The authors declare that no competing interests exist.

  8. Thiago S Moreira

    Department of Physiology and Biophysics, University of São Paulo, São Paulo, Brazil
    For correspondence
    tmoreira@icb.usp.br
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9789-8296

Funding

Fundação de Amparo à Pesquisa do Estado de São Paulo (2009/01236-4)

  • Ana C Takakura

Fundação de Amparo à Pesquisa do Estado de São Paulo (2015/23376-1)

  • Thiago S Moreira

NHLBI Division of Intramural Research (RO1HL132355)

  • José J Otero

Conselho Nacional de Desenvolvimento Científico e Tecnológico (302334/2019-0)

  • Thiago S Moreira

Conselho Nacional de Desenvolvimento Científico e Tecnológico (302288/2019-8)

  • Ana C Takakura

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

Reviewing Editor

  1. Muriel Thoby-Brisson, CNRS Université de Bordeaux, France

Ethics

Animal experimentation: This study was conducted in accordance with the University of Sao Paulo Institutional Animal Care and Use Committee guidelines (protocol number: 3618221019).

Version history

  1. Preprint posted: August 10, 2021 (view preprint)
  2. Received: August 17, 2021
  3. Accepted: November 14, 2022
  4. Accepted Manuscript published: November 17, 2022 (version 1)
  5. Version of Record published: November 23, 2022 (version 2)

Copyright

© 2022, Ferreira 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. Caroline B Ferreira
  2. Talita M Silva
  3. Phelipe E Silva
  4. Claudio L Castro
  5. Catherine Czeisler
  6. José J Otero
  7. Ana C Takakura
  8. Thiago S Moreira
(2022)
Phox2b mutation mediated by Atoh1 expression impaired respiratory rhythm and ventilatory responses to hypoxia and hypercapnia
eLife 11:e73130.
https://doi.org/10.7554/eLife.73130

Share this article

https://doi.org/10.7554/eLife.73130

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