Dysregulation of locus coeruleus development in congenital central hypoventilation syndrome.

Nobuta, Hiroko;Cilio, Maria Roberta;Danhaive, Olivier;Tsai, Hui-Hsin;Otero, José Javier;et.al.
(2015) Acta Neuropathologica — Vol. 130, n° 2, p. 171-183 (2015)

Files

2015_Nobuta_Acta_Neuropathol.pdf
  • Open Access
  • Adobe PDF
  • 2.87 MB
Download

Details

Authors
  • Nobuta, Hiroko
    Author
  • Cilio, Maria Roberta
    Author
  • Danhaive, Olivierorcid-logoUCLouvain
    Author
  • Tsai, Hui-Hsin
    Author
  • Otero, José Javier
    Author
Show more
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.
Affiliations
  • University of California, San FranciscoDepartment of Pediatrics

Citations

  • APA
  • Chicago
  • FWB

Nobuta, H., Cilio, M. R., Danhaive, O., Tsai, H.-H., Tupal, S., Chang, S. M., Murnen, A., Kreitzer, F., Bravo, V., Czeisler, C., Gokozan, H. N., Gygli, P., Bush, S., Weese-Mayer, D. E., Conklin, B., Yee, S.-P., Huang, E. J., Gray, P. A., Rowitch, D., & Otero, J. J. (2015). Dysregulation of locus coeruleus development in congenital central hypoventilation syndrome. Acta Neuropathologica, 130(2), 171-183. https://doi.org/10.1007/s00401-015-1441-0 (Original work published 2015)