title: Dysregulation of locus coeruleus development in congenital central hypoventilation syndrome.
abstract: Human congenital central hypoventilation syndrome (CCHS), resulting from mutations in transcription factor PHOX2B, manifests with impaired responses to hypoxemia and hypercapnia especially during sleep. To identify brainstem structures developmentally affected in CCHS, we analyzed two postmortem neonatal-lethal cases with confirmed polyalanine repeat expansion (PARM) or Non-PARM (PHOX2B∆8) mutation of PHOX2B. Both human cases showed neuronal losses within the locus coeruleus (LC), which is important for central noradrenergic signaling. Using a conditionally active transgenic mouse model of the PHOX2B∆8 mutation, we found that early embryonic expression (<E10.5) caused failure of LC neuronal specification and perinatal respiratory lethality. In contrast, later onset (E11.5) of PHOX2B∆8 expression was not deleterious to LC development and perinatal respiratory lethality was rescued, despite failure of chemosensor retrotrapezoid nucleus formation. Our findings indicate that early-onset mutant PHOX2B expression inhibits LC neuronal development in CCHS. They further suggest that such mutations result in dysregulation of central noradrenergic signaling, and therefore, potential for early pharmacologic intervention in humans with CCHS.
authors.affiliation: Department of Pediatrics, University of California San Francisco, 35 Medical Center Way, San Francisco, CA, 94143, USA.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Nobuta
authors.forename: Maria Roberta
authors.initials: MR
authors.lastname: Cilio
authors.forename: Olivier
authors.initials: O
authors.lastname: Danhaive
authors.forename: Hui-Hsin
authors.initials: HH
authors.lastname: Tsai
authors.forename: Srinivasan
authors.initials: S
authors.lastname: Tupal
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Chang
authors.forename: Alice
authors.initials: A
authors.lastname: Murnen
authors.forename: Faith
authors.initials: F
authors.lastname: Kreitzer
authors.forename: Verenice
authors.initials: V
authors.lastname: Bravo
authors.forename: Catherine
authors.initials: C
authors.lastname: Czeisler
authors.forename: Hamza Numan
authors.initials: HN
authors.lastname: Gokozan
authors.forename: Patrick
authors.initials: P
authors.lastname: Gygli
authors.forename: Sean
authors.initials: S
authors.lastname: Bush
authors.forename: Debra E
authors.initials: DE
authors.lastname: Weese-Mayer
authors.forename: Bruce
authors.initials: B
authors.lastname: Conklin
authors.forename: Siu-Pok
authors.initials: SP
authors.lastname: Yee
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Huang
authors.forename: Paul A
authors.initials: PA
authors.lastname: Gray
authors.forename: David
authors.initials: D
authors.lastname: Rowitch
authors.forename: José Javier
authors.initials: JJ
authors.lastname: Otero
mesh_terms: D017668:Age of Onset; D000818:Animals; D004195:Disease Models, Animal; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007040:Hypoventilation / Q000151:congenital* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D007231:Infant, Newborn; D007234:Infant, Premature; D008125:Locus Coeruleus / Q000254:growth & development* / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D055495:Neurogenesis / Q000502:physiology; D009474:Neurons / Q000473:pathology / Q000502:physiology; D012119:Respiration; D020182:Sleep Apnea, Central / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D046509:Tissue Culture Techniques; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D018398:Homeodomain Proteins; C109220:NBPhox protein; D014157:Transcription Factors