RET IN HUMAN-DEVELOPMENT AND ONCOGENESIS

Hirschsprung disease and the multiple endocrine neoplasia type 2 syndr omes are hereditary disorders related to the abnormal migration, proli feration or survival of neural crest cells and their derivatives. Hirs chsprung disease is a frequent disorder of the enteric nervous system, resulting in intestinal obstruction, The multiple endocrine neoplasia type 2 syndromes predispose to cancers of neural crest derivatives. B oth diseases are associated with heterozygous mutations in the RET pro to-oncogene. RET encodes a transmembrane receptor tyrosine kinase expr essed in neural crest lineages and whose ligand, glial-cell-line-deriv ed neurotrophic factor, has been very recently identified. In vitro ex pression studies demonstrate that while Hirschsprung disease mutations result in loss of function of the mutant RET tyrosine kinase, multipl e endocrine neoplasia type 2 mutations lead to its constitutive activa tion, Thus, the two 'faces' of RET, gain of function and loss of funct ion, each lead to a different syndrome, respectively: multiple endocri ne neoplasia type 2, a cancer syndrome, or Hirschsprung disease, a dev elopmental defect.