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

Elife. 2018 Jul 4:7:e38455. doi: 10.7554/eLife.38455.


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)) has 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.

Keywords: Atoh1; apnea; developmental biology; hypercapnia; hypoxia; mouse; neuroscience; respiration; respiratory chemoresponses.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Basic Helix-Loop-Helix Transcription Factors / deficiency*
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Biomarkers / metabolism
  • Caffeine / pharmacology
  • Cell Lineage / drug effects
  • Cell Survival / drug effects
  • Cerebellum / pathology
  • Cerebellum / physiopathology
  • Hypercapnia / complications*
  • Hypercapnia / metabolism*
  • Hypercapnia / physiopathology
  • Hypoxia / complications*
  • Hypoxia / metabolism*
  • Hypoxia / physiopathology
  • Mice, Knockout
  • Motor Neurons / drug effects
  • Motor Neurons / metabolism
  • Neurons / drug effects
  • Neurons / metabolism*
  • Respiration / drug effects
  • Respiratory Insufficiency / complications*
  • Respiratory Insufficiency / metabolism*
  • Respiratory Insufficiency / physiopathology


  • Atoh1 protein, mouse
  • Basic Helix-Loop-Helix Transcription Factors
  • Biomarkers
  • Caffeine