The enteric nervous system (ENS) derives from the neural crest and is crucial for multiple aspects of gut function. As the innervated intestine is a dynamically changing tissue over the lifespan, how the ENS is amplified in times of growth or repair is an important and clinically relevant question; however, whether and how continuous ENS neurogenesis occurs has remained stubbornly controversial. Wael Noor El-Nachef and Marianne Bronner now tackle this problem by analysing de novo ENS neurogenesis in the zebrafish intestine. First, hypothesised resident ENS progenitors or glia are not seen in the 3.5 days postfertilization zebrafish intestine: Sox10 and glial marker expression are absent, and Sox10-derived lineages are strictly neuronal. Photoconversion experiments show newly born enteric neurons appearing both in normal development and following laser ablation of existing neurons. Lineage-tracing experiments (based on timed dye injections and inducible transgenes) indicate that new enteric neurons derive from the late emigrating trunk neural crest, the population from which Schwann cell precursors are known to derive. Finally, treating fish with prucalopride (known to stimulate postnatal enteric neurogenesis in mice) increases de novo enteric neurogenesis in zebrafish larvae, in both developmental and injury contexts. Thus, the larval zebrafish ENS is expanded and repaired not by resident cell types but by trunk neural crest-derived Schwann cell precursors.
