“…In this issue, Nagashimada et al (4), in a truly remarkable study, have now provided a real insight into how a mutation in PHOX2B, a gene that encodes a paired homeodomain transcription factor that plays a critical role in the development of crest-derived autonomic neurons (5), can act in different cells in a gain-of-function or in a loss-of function manner. The gainof-function activity is tumorigenic, causing neuroblastomas (NBs) to arise in the sympathetic nervous system, while perversely synergizing with the loss-of-function effect to disrupt neurogenesis, sympathetic gangliogenesis, and crest cell colonization of the terminal bowel, which becomes aganglionic (Hirschsprung disease [HSCR]).…”