Phox2b mutation mediated by Atoh1 expression impaired respiratory rhythm and ventilatory responses to hypoxia and hypercapnia
- University of São Paulo, Brazil
- The Ohio State University, United States
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
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.
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).
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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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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