Genetic identification of novel medullary neurons underlying congenital central hypoventilation syndrome

Author:

Cui KeORCID,Xia YilingORCID,Patnaik AbhisarikaORCID,Lowenstein Elijah D.ORCID,Isik Eser GöksuORCID,Knorz Adrian L.ORCID,Airaghi LauraORCID,Crotti MichelaORCID,Studer Michèle,Rijli Filippo M.ORCID,Nothwang Hans G.ORCID,Hernandez-Miranda Luis R.ORCID

Abstract

AbstractCongenital Central Hypoventilation Syndrome (CCHS) is a rare, but life-threatening, respiratory disorder that is classically diagnosed in children. This disease is characterized by pronounced alveolar hypoventilation and diminished chemoreflexes, particularly to abnormally high levels of arterial pCO2. Mutations in the transcription factorsPHOX2BandLBX1have been identified in CCHS patients, but the dysfunctional circuit responsible for this disease remains unknown. Here, we show that distinct sets of medullary neurons co-expressing both transcription factors (dB2 neurons) account for specific respiratory functions and phenotypes seen in CCHS. By combining murine intersectional chemogenetics, intersectional labeling, and the selective targeting of the CCHS disease-causingLbx1FSmutation to specific subgroups of dB2 neurons, we uncovered novel sets of these cells key for i) respiratory tidal volumes and the hypercarbic reflex, ii) neonatal respiratory stability and iii) neonatal survival. These data provide functional evidence for the essential role of dB2 neurons in neonatal respiratory physiology and will be instrumental for the development of therapeutic strategies for the management of CCHS. In summary, our work uncovers new neural components of the central circuit regulating breathing and establishes dB2 neuron dysfunction to be causative of CCHS.

Publisher

Cold Spring Harbor Laboratory

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