The visceral reflex circuits are responsible for modulating vital bodily functions, including breathing, digestion and heartbeat. New findings by Dauger et al., reported in Development, reveal a specific role for the homeodomain transcription factor Phox2b in the construction of these circuits.

The same team previously showed that the Phox2b gene is required for the development of the efferent (motor) arm of the visceral nervous system, and their new data indicate that the gene is also required for the development of afferent (sensory) pathways. In homozygous Phox2b-knockout mice, the nucleus of the solitary tract (nTS) — a hindbrain nucleus that receives and relays sensory information from the visceral organs — fails to differentiate. In addition, sensory structures that project to the nTS, including sensory ganglia, the area postrema and the carotid body, are absent in mice that lack Phox2b.

In humans, heterozygous mutations in PHOX2B are associated with congenital central hypoventilation syndrome (CCHS), a childhood condition in which the autonomic control of breathing is impaired, particularly during the rapid eye movement phase of sleep. Dauger et al. showed that heterozygous Phox2b-knockout mice also show defects in breathing control during early postnatal life. In particular, young mutant animals showed a reduced ventilatory response to raised levels of carbon dioxide (hypercapnia). So, the heterozygous Phox2b knockout seems to provide a good animal model for CCHS.

Phox2b is a rare example of a gene that controls the development of a specific circuit, which is constructed from different neuronal subtypes from diverse origins, including the neural tube, neural crest and epibranchial placodes. This poses an intriguing question: how does the developing embryo bring the Phox2b-expressing cells into contact to make the appropriate synaptic connections? Dauger et al. suggest that Phox2b might regulate the expression of molecules that are required for axon guidance and/or neuronal migration, and an appropriately timed inactivation of Phox2b (to bypass its requirement for earlier stages of neuronal differentiation) could provide answers to this question.