Phox2b mutation mediated by Atoh1 expression impaired respiratory rhythm and ventilatory responses to hypoxia and hypercapnia
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 is incompletely u...
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| Format: | Article |
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eLife Sciences Publications Ltd
2022-11-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/73130 |
| _version_ | 1811179842834530304 |
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| author | Caroline B Ferreira Talita M Silva Phelipe E Silva Claudio L Castro Catherine Czeisler José J Otero Ana C Takakura Thiago S Moreira |
| author_facet | Caroline B Ferreira Talita M Silva Phelipe E Silva Claudio L Castro Catherine Czeisler José J Otero Ana C Takakura Thiago S Moreira |
| author_sort | Caroline B Ferreira |
| collection | DOAJ |
| description | 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 is 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 nucleus [RTN] region) 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. |
| first_indexed | 2024-04-11T06:40:20Z |
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| institution | Directory Open Access Journal |
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| language | English |
| last_indexed | 2024-04-11T06:40:20Z |
| publishDate | 2022-11-01 |
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| spelling | doaj.art-507e8eb3bee8488b9368b47ae8f36d0e2022-12-22T04:39:33ZengeLife Sciences Publications LtdeLife2050-084X2022-11-011110.7554/eLife.73130Phox2b mutation mediated by Atoh1 expression impaired respiratory rhythm and ventilatory responses to hypoxia and hypercapniaCaroline B Ferreira0Talita M Silva1Phelipe E Silva2Claudio L Castro3Catherine Czeisler4José J Otero5Ana C Takakura6Thiago S Moreira7https://orcid.org/0000-0002-9789-8296Department of Pharmacology, Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, Sao Paulo, BrazilDepartment of Physiology and Biophysics, Instituto de Ciencias Biomedicas, University of Sao Paulo, Sao Paulo, BrazilDepartment of Physiology and Biophysics, Instituto de Ciencias Biomedicas, University of Sao Paulo, Sao Paulo, BrazilDepartment of Physiology and Biophysics, Instituto de Ciencias Biomedicas, University of Sao Paulo, Sao Paulo, BrazilDepartment of Pathology, College of Medicine, Ohio State University, Columbus, United StatesDepartment of Pathology, College of Medicine, Ohio State University, Columbus, United StatesDepartment of Pharmacology, Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, Sao Paulo, BrazilDepartment of Physiology and Biophysics, Instituto de Ciencias Biomedicas, University of Sao Paulo, Sao Paulo, BrazilMutations 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 is 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 nucleus [RTN] region) 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.https://elifesciences.org/articles/73130hypercapniahypoxiaventilationphox2bretrotrapezoid nucleus |
| spellingShingle | Caroline B Ferreira Talita M Silva Phelipe E Silva Claudio L Castro Catherine Czeisler José J Otero Ana C Takakura Thiago S Moreira Phox2b mutation mediated by Atoh1 expression impaired respiratory rhythm and ventilatory responses to hypoxia and hypercapnia eLife hypercapnia hypoxia ventilation phox2b retrotrapezoid nucleus |
| title | Phox2b mutation mediated by Atoh1 expression impaired respiratory rhythm and ventilatory responses to hypoxia and hypercapnia |
| title_full | Phox2b mutation mediated by Atoh1 expression impaired respiratory rhythm and ventilatory responses to hypoxia and hypercapnia |
| title_fullStr | Phox2b mutation mediated by Atoh1 expression impaired respiratory rhythm and ventilatory responses to hypoxia and hypercapnia |
| title_full_unstemmed | Phox2b mutation mediated by Atoh1 expression impaired respiratory rhythm and ventilatory responses to hypoxia and hypercapnia |
| title_short | Phox2b mutation mediated by Atoh1 expression impaired respiratory rhythm and ventilatory responses to hypoxia and hypercapnia |
| title_sort | phox2b mutation mediated by atoh1 expression impaired respiratory rhythm and ventilatory responses to hypoxia and hypercapnia |
| topic | hypercapnia hypoxia ventilation phox2b retrotrapezoid nucleus |
| url | https://elifesciences.org/articles/73130 |
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