Loss of Atoh1 from neurons regulating hypoxic and hypercapnic chemoresponses causes neonatal respiratory failure in mice

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Abstract

Atoh1-null mice die at birth from respiratory failure, but the precise cause has remained elusive. Loss of Atoh1 from various components of the respiratory circuitry (e.g., the retrotrapezoid nucleus (RTN)) have so far produced at most 50% neonatal lethality. To identify other Atoh1-lineage neurons that contribute to postnatal survival, we examined parabrachial complex neurons derived from the rostral rhombic lip (rRL) and found that they are activated during respiratory chemochallenges. Atoh1-deletion from the rRL does not affect survival, but causes apneas and respiratory depression during hypoxia, likely due to loss of projections to the preBötzinger Complex and RTN. Atoh1 thus promotes the development of the neural circuits governing hypoxic (rRL) and hypercapnic (RTN) chemoresponses, and combined loss of Atoh1 from these regions causes fully penetrant neonatal lethality. This work underscores the importance of modulating respiratory rhythms in response to chemosensory information during early postnatal life.

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All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 2, 3, 4 and 6.

Article and author information

Author details

Meike E van der Heijden

Department of Neuroscience, Baylor College of Medicine, Houston, United States

Competing interests
No competing interests declared.
Huda Y Zoghbi

Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, United States

For correspondence
hzoghbi@bcm.edu

Competing interests
Huda Y Zoghbi, Senior editor, eLife.

"This ORCID iD identifies the author of this article:" 0000-0002-0700-3349

Funding

American Heart Association (Predoctoral fellowship award number 17PRE33660616)

Meike E van der Heijden

Howard Hughes Medical Institute

Huda Y Zoghbi

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 animals were housed in a Level 3, AALAS-certified facility on a 14hr light cycle. Husbandry, housing, euthanasia, and experimental guidelines were reviewed and approved by the Institutional Animal Care and Use Committee (IACUC) of Baylor College of Medicine (protocol number: AN1013).

Copyright

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.