CO2 in the spotlight

W e breathe to get oxygen and to get rid of carbon dioxide (CO2). The precise monitoring of CO2 levels in the body is crucial because too much of it makes our blood acidic, which can have toxic effects. Under normal resting conditions, the concentration of CO2 controls our respiratory rate. For example, in most animals, including humans, high levels of CO2 lead to faster breathing. Moreover, having a weakened response to CO2 can be a life-threatening condition (Guyenet et al., 2010). In spite of many years of research, the identity of the neurons involved in sensing CO2, and thus in controlling breathing, has been controversial (Guyenet et al., 2013). Now, in eLife, JeanFrancois Brunet of the Ecole Normale Supérieure and colleagues from France, Japan and Sweden report that neurons in the retrotrapezoid nucleus in the brainstem make up the CO2 sensor. The retrotrapezoid nucleus is a tiny structure located in the ventral side of the brainstem—that is, it is towards the front of the brainstem in humans, but on the underside in mice and most other animals (Figure 1). These neurons rhythmically send signals to other neurons at normal body pH, and increase the rate at which they fire when the pH of the blood becomes acidic (Goridis and Brunet, 2010). The neurons in the retrotrapezoid nucleus are also directly connected to the preBötzinger complex (the structure in the brainstem that generates the breathing rhythm) and can adjust its activity. Mouse models in which the development of retrotrapezoid neurons is disrupted display slow breathing and have weakened, or blunted, responses to acidification (Sieber et al., 2007; Dubreuil et al., 2008, 2009; Goridis et al., 2010; Ramanantsoa et al., 2011). However, a recent study reported that retrotrapezoid neurons, particularly in newborn mice, might not be required for CO2 sensitivity (Huang et al., 2012). This cast doubts on the precise role of the retrotrapezoid nucleus. Retrotrapezoid neurons send signals that activate, or excite, other neurons. Brunet and colleagues—who include Pierre-Louis Ruffault as first author—combined mouse genetics and optogenetic techniques to selectively stimulate specific retrotrapezoid neurons with light (Ruffault et al., 2015). This revealed that retrotrapezoid neurons adjust the activity of the phrenic nerve—the motor nerve that controls the muscles involved in breathing—by activating phrenic motor neurons via the preBötzinger complex (Figure 1). These results provide conclusive evidence of a direct association between the activity of retrotrapezoid neurons and respiratory motor neurons. Retrotrapezoid neurons develop from progenitor cells located in the dorsal side of the brainstem (that is, towards the back of the brainstem in humans, but on the topside in mice). At first, these progenitor cells express a transcription factor called Phox2b. Later in their Copyright Hernandez-Miranda and Birchmeier. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.