C-cell hyperplasia, pheochromocytoma and sympathoadrenal malformation in amouse model of multiple endocrine neoplasia type 2B

Dominantly inherited multiple endocrine neoplasia type 2B (MEN2B) is charac terized by tumors of the thyroid C-cells and adrenal chromaffin cells, toge ther with ganglioneuromas of the gastrointestinal tract and other developme ntal abnormalities. Most cases are caused by substitution of threonine for Met918 in the RET receptor tyrosine kinase, which is believed to convert th e RET gene to an oncogene by altering the enzyme's substrate specificity. W e report the production of a mouse model of MEN2B by introduction of the co rresponding mutation into the ret gene. Mutant mice displayed C-cell hyperp lasia and chromaffin cell hyperplasia progressing to pheochromocytoma. Homo zygotes did not develop gastrointestinal ganglioneuromas, but displayed gan glioneuromas of the adrenal medulla, enlargement of the associated sympathe tic ganglia and a male reproductive defect. Surprisingly, homozygotes did n ot display any developmental defects attributable to a loss-of-function mut ation. Thus, while our results support the conclusion that the Met918Thr su bstitution is responsible for MEN2B, they suggest that the substrate specif icity of the RET kinase does not interfere with its normal role in the deve lopment of the kidneys and enteric nervous system.