title: Ventilatory response to hyperoxia in newborn mice heterozygous for the transcription factor Phox2b.
abstract: Heterozygous mutations of the transcription factor PHOX2B have been found in most patients with central congenital hypoventilation syndrome, a rare disease characterized by sleep-related hypoventilation and impaired chemosensitivity to sustained hypercapnia and sustained hypoxia. PHOX2B is a master regulator of autonomic reflex pathways, including peripheral chemosensitive pathways. In the present study, we used hyperoxic tests to assess the strength of the peripheral chemoreceptor tonic drive in Phox2b+/-newborn mice. We exposed 69 wild-type and 67 mutant mice to two hyperoxic tests (12-min air followed by 3-min 100% O2) 2 days after birth. Breathing variables were measured noninvasively using whole body flow plethysmography. The initial minute ventilation decrease was larger in mutant pups than in wild-type pups: -37% (SD 13) and -25% (SD 18), respectively, P<0.0001. Furthermore, minute ventilation remained depressed throughout O2 exposure in mutants, possibly because of their previously reported impaired CO2 chemosensitivity, whereas it returned rapidly to the normoxic level in wild-type pups. Hyperoxia considerably increased total apnea duration in mutant compared with wild-type pups (P=0.0001). A complementary experiment established that body temperature was not influenced by hyperoxia in either genotype group and, therefore, did not account for genotype-related differences in the hyperoxic ventilatory response. Thus partial loss of Phox2b function by heterozygosity did not diminish the tonic drive from peripheral chemoreceptors.
authors.affiliation: INSERM U676, Hôpital Robert-Debré, Université Paris, France.
authors.forename: N
authors.initials: N
authors.lastname: Ramanantsoa
authors.forename: V
authors.initials: V
authors.lastname: Vaubourg
authors.forename: S
authors.initials: S
authors.lastname: Dauger
authors.forename: B
authors.initials: B
authors.lastname: Matrot
authors.forename: G
authors.initials: G
authors.lastname: Vardon
authors.forename: Z
authors.initials: Z
authors.lastname: Chettouh
authors.forename: C
authors.initials: C
authors.lastname: Gaultier
authors.forename: C
authors.initials: C
authors.lastname: Goridis
authors.forename: J
authors.initials: J
authors.lastname: Gallego
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001049:Apnea / Q000235:genetics / Q000503:physiopathology; D001831:Body Temperature / Q000235:genetics / Q000502:physiology; D005260:Female; D006579:Heterozygote; D018398:Homeodomain Proteins / Q000235:genetics*; D018496:Hyperoxia / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D010993:Plethysmography, Whole Body; D012123:Pulmonary Ventilation / Q000235:genetics / Q000502:physiology*; D013990:Tidal Volume / Q000235:genetics / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D018398:Homeodomain Proteins; C109220:NBPhox protein; D014157:Transcription Factors