<i>Phox2b</i> mutation mediated by <i>Atoh1</i> expression impaired respiratory rhythm and ventilatory responses to hypoxia and hypercapnia.

Abstract

Mutations in the transcription factor <i>Phox2b</i> cause congenital central hypoventilation syndrome (CCHS). The syndrome is characterized by hypoventilation and inability to regulate breathing to maintain adequate O₂ and CO₂ levels. The mechanism by which CCHS impact respiratory control is incompletely understood, and even less is known about the impact of the non-polyalanine repeat expansion mutations (NPARM) form. Our goal was to investigate the extent by which NPARM <i>Phox2b</i> mutation affect (a) respiratory rhythm; (b) ventilatory responses to hypercapnia (HCVR) and hypoxia (HVR); and (c) number of chemosensitive neurons in mice. We used a transgenic mouse line carrying a conditional <i>Phox2b^Δ8</i> mutation (same found in humans with NPARM CCHS). We crossed them with <i>Atoh1^cre</i> mice to introduce mutation in regions involved with respiratory function and central chemoreflex control. Ventilation was measured by plethysmograph during neonatal and adult life. In room air, mutation in neonates and adult did not greatly impact basal ventilation. However, <i>Phox2b^Δ8</i>, <i>Atoh1^cre</i> increased breath irregularity in adults. The HVR and HCVR were impaired in neonates. The HVR, but not HCVR, was still partially compromised in adults. The mutation reduced the number of Phox2b⁺/TH^--expressing neurons as well as the number of fos-activated cells within the ventral parafacial region (also named retrotrapezoid nucleus [RTN] region) induced by hypercapnia. Our data indicates that <i>Phox2b^Δ8</i> mutation in <i>Atoh1</i>-expressing cells impaired RTN neurons, as well as chemoreflex under hypoxia and hypercapnia specially early in life. This study provided new evidence for mechanisms related to NPARM form of CCHS neuropathology.