The RET tyrosine kinase signaling pathway plays a major role in ENS migration, along with its ligands GDNF and NTN. The EDNRB G-protein coupled receptor together with its ligand ET3 and endothelin cleavage enzyme ECE-1 forms a separate signaling pathway important in ENS development. The RET and EDNRB signaling pathways appear interact with an additive effect through an as yet to be described mechanism. PHOX2B is a transcriptional regulator of the RET gene and SOX10 appears to be a transcriptional regulator of both RET and EDNRB genes. The complex regulation of the genes in each pathway, combined with the cross-signaling between pathways and the effects on ENS migration is the subject of ongoing investigations[8, 9].