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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-015-1441-0) contains supplementary material, which is available to authorized users.

Brainstem catecholaminergic neurones and breathing control during postnatal development in male and female rats

“…Furthermore, animals mutant for the Phox2a transcription factor (which causes significant neuronal loss of noradrenergic neurones, mainly in the A6 region) present dysregulation of noradrenergic signalling and ventilation impairment, similar to that observed in patients with congenital central hypoventilation syndrome (Nobuta et al . ). Sudden infant death syndrome (SIDS) victims may frequently present brainstem noradrenergic deficits (Ozand & Tildon, ; Denoroy et al .…”

Respiratory and autonomic dysfunction in congenital central hypoventilation syndrome

“…Several idiosyncrasies about the PHOX2B locus require special consideration for the generation of conditional experimental models of PARM CCHS (Ramanantsoa et al 2011) and NPARM CCHS (Nobuta et al 2015). The primary structures of mouse and human PHOX2B protein are identical, yet significant differences exist at the genomic level.…”

“…The only histopathological findings of CCHS with confirmed PHOX2B mutations was reported by Nobuta et al (2015). This data set included two CCHS patients, one PARM and one NPARM (Fig.…”

“…Although these in vivo and postmortem analyses of CCHS patients provide insight into the pathological processes afflicted by CCHS patients, the nature of these does not allow one to incisively test hypotheses regarding which pathological processes represent developmental syndrome versus a developmental sequence. For these reasons, we developed a humanized NPARM murine experimental model based on the NPARM patients described by Nobuta et al (2015). In this experiment, we used Hprt-cre interbreeding to evaluate the neuropathology of mice showing early recombination of the PHOX2B 20/E3-cKi-⌬8-ires-GFP locus and compared these findings with recombination in later stages of CNS development with BLBP1-cre mice.…”

“…The respiratory symptoms of the disease suggest that the central respiratory controller located in the pre-Bötz-inger complex of CCHS patients is largely intact but that the brain of these individuals lacks neurons that are either uniquely specialized in detecting CO 2 or are specialized in funneling the excitatory influence of CO 2 to the respiratory controller. The mouse models of the disease suggest that these missing neurons could be the RTN neurons (Dubreuil et al 2008;Goridis et al 2010;Nobuta et al 2015;Ramanantsoa et al 2011).…”