RET overactivation leads to concurrent Hirschsprung disease and intestinal ganglioneuromas

Appropriately balanced RET signaling is of critical importance during embryonic neural crest cell migration, proliferation, and differentiation. RET deficiency, for example, leads to intestinal aganglionosis (Hirschsprung disease), while overactive RET can lead to multiple endocrine neoplasia (MEN) syndromes. Some RET mutations are associated with both intestinal aganglionosis and MEN-associated tumors. This seemingly paradoxical occurrence has led to speculation of a “Janus mutation” in RET that causes overactivation or impairment of RET activity depending on the cellular context. Using an intestinal catenary culture system to test the effects of GDNF-mediated RET activation, we demonstrate the concurrent development of distal colonic aganglionosis and intestinal ganglioneuromas. Interestingly, the tumors induced by GDNF stimulation contain enteric neuronal progenitors capable of reconstituting an enteric nervous system when transplanted into a normal developmental environment. These results suggest that a Janus mutation may not be required to explain co-existing Hirschsprung disease and MEN-associated tumors, but rather that RET overstimulation alone is enough to cause both phenotypes. The results also suggest that reprogramming tumor cells toward nonpathological fates may represent a possible therapeutic avenue for MEN-associated neoplasms.