A human mutation in Phox2b causes lack of CO2 chemosensitivity, fatal central apnea, and specific loss of parafacial neurons

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.