The RET receptor tyrosine kinase: activation, signalling and significance in neural development and disease

The RET receptor tyrosine kinase was first identified in a screen for human oncogenes and has subsequently been linked to several human syndromes: Hirschprung's disease, multiple endocrine neoplasia types 2A and 2B and familial thyroid carcinoma. Interestingly, all of the tissues affected by mutations in RET are derived from the neural crest during development. RET transduces a signal following activation by ligands of the glial cell line-derived neurotrophic factor (GDNF) family of neurotrophins which currently comprises GDNF, neuturin (NTN), artemin (ART) and persephin (PSP). To activate RET they form a tripartite complex with RET and a member of a family of four extracellular, GPI-linked alpha receptors (GFRα1–4). Specificity is achieved by each GFRα binding only one member of the GDNF family with high affinity. Current evidence indicates that signal transduction by RET activates several second messenger systems including the PLCγ, Ras, JNK and inositol phosphate pathways. Targeted mutagenesis in transgenic mice has shown that Ret, GFRα1 and GDNF are required for multiple developmental events including development of the enteric nervous system (ENS) affected in Hirschsprung's disease. We describe experiments in chick neural crest cells which provide evidence for the normal function of RET and the basis of the defect in Hirschsprung's disease.