title: Breathing without CO(2) chemosensitivity in conditional Phox2b mutants.
abstract: Breathing is a spontaneous, rhythmic motor behavior critical for maintaining O(2), CO(2), and pH homeostasis. In mammals, it is generated by a neuronal network in the lower brainstem, the respiratory rhythm generator (Feldman et al., 2003). A century-old tenet in respiratory physiology posits that the respiratory chemoreflex, the stimulation of breathing by an increase in partial pressure of CO(2) in the blood, is indispensable for rhythmic breathing. Here we have revisited this postulate with the help of mouse genetics. We have engineered a conditional mouse mutant in which the toxic PHOX2B(27Ala) mutation that causes congenital central hypoventilation syndrome in man is targeted to the retrotrapezoid nucleus, a site essential for central chemosensitivity. The mutants lack a retrotrapezoid nucleus and their breathing is not stimulated by elevated CO(2) at least up to postnatal day 9 and they barely respond as juveniles, but nevertheless survive, breathe normally beyond the first days after birth, and maintain blood PCO(2) within the normal range. Input from peripheral chemoreceptors that sense PO(2) in the blood appears to compensate for the missing CO(2) response since silencing them by high O(2) abolishes rhythmic breathing. CO(2) chemosensitivity partially recovered in adulthood. Hence, during the early life of rodents, the excitatory input normally afforded by elevated CO(2) is dispensable for life-sustaining breathing and maintaining CO(2) homeostasis in the blood.
authors: Institut National de la Santé et de la Recherche Médicale (INSERM) U676, Hôpital Robert Debré, 75019 Paris, France.
authors: Nelina
authors: N
authors: Ramanantsoa
authors: Marie-Rose
authors: MR
authors: Hirsch
authors: Muriel
authors: M
authors: Thoby-Brisson
authors: Véronique
authors: V
authors: Dubreuil
authors: Julien
authors: J
authors: Bouvier
authors: Pierre-Louis
authors: PL
authors: Ruffault
authors: Boris
authors: B
authors: Matrot
authors: Gilles
authors: G
authors: Fortin
authors: Jean-François
authors: JF
authors: Brunet
authors: Jorge
authors: J
authors: Gallego
authors: Christo
authors: C
authors: Goridis
mesh_terms: D000375:Aging / Q000502:physiology; D000483:Alleles; D000818:Animals; D001784:Blood Gas Analysis; D001933:Brain Stem / Q000196:embryology / Q000502:physiology; D002245:Carbon Dioxide / Q000378:metabolism*; D051767:Early Growth Response Protein 2 / Q000235:genetics; D055724:Electrophysiological Phenomena; D005091:Exons / Q000235:genetics; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics* / Q000502:physiology*; D007040:Hypoventilation / Q000151:congenital / Q000503:physiopathology; D007150:Immunohistochemistry; D051379:Mice; D009154:Mutation / Q000502:physiology; D010100:Oxygen / Q000097:blood; D010991:Plethysmography; D011247:Pregnancy; D012119:Respiration / Q000235:genetics*; D020182:Sleep Apnea, Central / Q000503:physiopathology; D013116:Spinal Cord / Q000196:embryology / Q000502:physiology; D013534:Survival; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology*
chemical_list: D051767:Early Growth Response Protein 2; C497327:Egr2 protein, mouse; D018398:Homeodomain Proteins; C109220:NBPhox protein; D014157:Transcription Factors; D002245:Carbon Dioxide; D010100:Oxygen