TY - JOUR
T1 - Dysregulation of locus coeruleus development in congenital central hypoventilation syndrome
AU - Nobuta, Hiroko
AU - Cilio, Maria Roberta
AU - Danhaive, Olivier
AU - Tsai, Hui Hsin
AU - Tupal, Srinivasan
AU - Chang, Sandra M.
AU - Murnen, Alice
AU - Kreitzer, Faith
AU - Bravo, Verenice
AU - Czeisler, Catherine
AU - Gokozan, Hamza Numan
AU - Gygli, Patrick
AU - Bush, Sean
AU - Weese-Mayer, Debra E.
AU - Conklin, Bruce
AU - Yee, Siu Pok
AU - Huang, Eric J.
AU - Gray, Paul A.
AU - Rowitch, David
AU - Otero, José Javier
N1 - Funding Information:
The authors thank Arturo Alvarez-Buylla, A. James Barkovich and Bernard Lo for comments on the manuscript, Marta Couce for facilitating procurement of CCHS autopsy tissue, Kanji Nobuta for artistic assistance, and the Gladstone Stem Cell Core Facility for technical assistance. H.N. is grateful to the European Leukodystrophy Association for a postdoctoral fellowship. J.J.O. was supported by California Institute for Regenerative Medicine Clinical Scholar Award (TG2-01153), UCSF-CTSI Grant Number UL1RR024131, and OSU CRMCBT Grant Number 8UL1TR000090-05. This work was funded by NIH Grants HL098179, HL108677, HL100406 (to B.C.), HL089742 (to P.A.G., S.T.), OD010927 (to E.J. H.) and NS083513 (to D.H.R.). E.J.H acknowledges the University of California Pediatric Neuropathology Consortium. D.H.R. is a Howard Hughes Medical Institute Investigator.
Publisher Copyright:
© 2015, The Author(s).
PY - 2015/8/25
Y1 - 2015/8/25
N2 - 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.
AB - 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.
KW - Congenital central hypoventilation syndrome
KW - Locus coeruleus
KW - Noradrenergic system
KW - PHOX2B
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U2 - 10.1007/s00401-015-1441-0
DO - 10.1007/s00401-015-1441-0
M3 - Article
C2 - 25975378
AN - SCOPUS:84937815404
SN - 0001-6322
VL - 130
SP - 171
EP - 183
JO - Acta Neuropathologica
JF - Acta Neuropathologica
IS - 2
ER -