A human mutation in Phox2b causes lack of CO ₂ chemosensitivity, fatal central apnea, and specific loss of parafacial neurons

Abstract

Breathing is maintained and controlled by a network of neurons in the brainstem that generate respiratory rhythm and provide regulatory input. Central chemoreception, the mechanism for CO2 detection that provides an essential stimulatory input, is thought to involve neurons located near the medullary surface, whose nature is controversial. Good candidates are serotonergic medullary neurons and glutamatergic neurons in the parafacial region. Here, we show that mice bearing a mutation in Phox2b that causes congenital central hypoventilation syndrome in humans breathe irregularly, do not respond to an increase in CO2, and die soon after birth from central apnea. They specifically lack Phox2b-expressing glutamatergic neurons located in the parafacial region, whereas other sites known or supposed to be involved in the control of breathing are anatomically normal. These data provide genetic evidence for the essential role of a specific population of medullary interneurons in driving proper breathing at birth and will be instrumental in understanding the etiopathology of congenital central hypoventilation syndrome.brainstem ͉ congenital central hypoventilation syndrome ͉ neurodegenerative disease ͉ respiration

Breathing withPhox2b

“…First, neurons of the adult rat RTN, defined physiologically by their responsiveness to CO 2 in vivo (Mulkey et al 2004;reviewed in Guyenet 2008), and phenotyped as Vglut2 þ (but negative for glutamate decarboxylase and tyrosine hydroxylase) and located at the ventral medullary surface under the facial nucleus and extending approximately 500 mm caudal to it, were all found to express Phox2b (Stornetta et al 2006). Second, inspection of the hindbrain of Phox2b 27Ala/þ newborn mice that have no response to hypercapnia ( §2) showed that there was an 85 per cent depletion of the Phox2b þ /Vglut2 þ RTN neurons (Dubreuil et al 2008). This observation held true for embryonic day (E)15.5 embryos, ruling out post-natal hypoxic injury as a cause.…”

“…Transmitting chimeras produced heterozygous pups (Phox2b þ/27Ala ) that died soon after birth from respiratory failure (Dubreuil et al 2008). Plethysmography performed prior to death revealed an absence of response to hypercapnia.…”

“…In an attempt to model CCHS, the most frequent mutation, a 7-residue expansion of the poly-Alanine stretch, was introduced in mice (Dubreuil et al 2008). Transmitting chimeras produced heterozygous pups (Phox2b þ/27Ala ) that died soon after birth from respiratory failure (Dubreuil et al 2008).…”

Task2 potassium channels set central respiratory CO 2 and O 2 sensitivity

“…In mice carrying a Phox2b mutation that causes the human congenital central hypoventilation syndrome (13), all Task2-positive RTN neurons were lost. In plethysmography and in vitro en bloc preparation, Task2 −/− mice showed compromised central respiratory adaptation to hypoxia and hypercapnia.…”

“…Recently, a mouse model that carries a mutation of the transcription factor Phox2b, which causes congenital central hypoventilation syndrome in humans, was engineered. A specific loss of a population of Phox2b-expressing RTN/pFRG neurons was associated with early death of these newborn mice due to the lack of the ventilatory response to hypercapnia (13).…”