PHOX2B in respiratory control: lessons from congenital central hypoventilation syndrome and its mouse models

Respir Physiol Neurobiol. 2009 Aug 31;168(1-2):125-32. doi: 10.1016/j.resp.2009.03.005. Epub 2009 Mar 21.


Phox2b is a master regulator of visceral reflex circuits. Its role in the control of respiration has been highlighted by the identification of heterozygous PHOX2B mutations as the cause of Central Congenital Hypoventilation Syndrome (CCHS), a rare disease defined by the lack of CO(2) responsiveness and of breathing automaticity in sleep. Phox2b(27Ala/+) mice that bear a frequent CCHS-causing mutation do not respond to hypercapnia and die in the first hour after birth from central apnoea. They are therefore a reliable animal model for CCHS. Neurons of the retrotrapezoïd nucleus/parafacial respiratory group (RTN/pFRG) were found severely depleted in these mice and no other neuronal loss could be identified. Physiological experiments show that RTN/pFRG neurons are crucial to driving proper breathing at birth and are necessary for central chemoreception and the generation of a normal respiratory rhythm. To date, the reason for the selective vulnerability of RTN/pFRG neurons to PHOX2B protein dysfunction remains unexplained.

MeSH terms

  • Animals
  • Animals, Newborn
  • Autonomic Nervous System Diseases / genetics
  • Carbon Dioxide / metabolism
  • Chemoreceptor Cells / physiology
  • Disease Models, Animal*
  • Homeodomain Proteins / genetics*
  • Humans
  • Infant
  • Infant, Newborn
  • Mice
  • Mutation / genetics*
  • Oxygen / metabolism
  • Peptides / genetics
  • Respiration / genetics*
  • Respiratory Center / pathology
  • Sleep Apnea, Central / congenital
  • Sleep Apnea, Central / genetics*
  • Sleep Apnea, Central / pathology
  • Sleep Apnea, Central / physiopathology*
  • Temperature
  • Transcription Factors / deficiency
  • Transcription Factors / genetics*


  • Homeodomain Proteins
  • NBPhox protein
  • Peptides
  • Transcription Factors
  • Carbon Dioxide
  • polyalanine
  • Oxygen