Ganglioneuromas and renal anomalies are induced by activated RETMEN2B in transgenic mice

Multiple endocrine neoplasia type 2B (MEN2B) is an autosomal dominant syndr ome characterized by the development of medullary thyroid carcinoma, pheoch romocytomas, musculoskeletal anomalies and mucosal ganglioneuromas, MEN2B i s caused by a specific mutation (Met918 --> Thr) in the RET receptor tyrosi ne kinase, Different mutations of RET lead to other conditions including ME N2A, familial medullary thyroid carcinoma and intestinal aganglionosis (Hir schsprung disease). Transgenic mice were created using the dopamine beta-hy droxylase promoter to direct expression of RETMEN2B the developing sympathe tic and enteric nervous systems and the adrenal medulla, D beta H-RETMEN2B transgenic mice developed benign neuroglial tumors, histologically identica l to human ganglioneuromas, in their sympathetic nervous systems and adrena l glands. The enteric nervous system was not affected. The neoplasms in D b eta H-RETMEN2B mice were similar to benign neuroglial tumors induced in tra nsgenic mice by activated Ras expression under control of the same promoter , Levels of phoshorylated MAP kinase were not increased in the RETMEN2B-ind uced neurolgial proliferations, suggesting that alternative pathways may pl ay a role in the pathogenesis of these lesions, Transgenic mice with the hi ghest levels of D beta H-RETMEN2B expression, unexpectedly developed renal malformations analogous to those reported with loss of function mutations i n the Ret gene.