Non-neural crest lineage contributions to the enteric nervous system: Moving a 50 year conclusion

It is considered an established fact that the entirety of the autonomic nervous system, including the enteric nervous system (ENS), is derived from neural crest. This conclusion is based on classical quail-chick grafting studies conducted by Le Douarin and colleagues in the 1970s, and results consistent with this conclusion have been obtained in mouse using recombinase-based neural crest-specific lineage tracing and gene knockout. Recently, additional sources that also contribute to the ENS have been implicated. Because these observations run counter to the neural crest-exclusive view, here we revisit the original avian studies by Le Douarin and subsequent mouse studies that in fact did not exclude additional lineage contributions to the ENS, particularly in the distal colon. We also review the evidence from mice supporting an ENS contribution from several non-neural crest lineages, including the placodes for which the evidence for contribution to the colonic ENS is particularly strong. Hirschsprung disease is a severe condition in which the colonic ENS is deficient at birth, and cell transplantation strategies for Hirschsprung disease are in many cases predicated on the assumption that all of the missing ENS components are neural crest-derived. Thus, beyond the general interest in this fundamental feature of developmental biology, it is particularly important that investigators who pursue cell transplantation approaches for Hirschsprung disease or therapeutic approaches for any ENS-associated condition take these observations into consideration.