Rajan_2001_Pediatr.Dev.Pathol_4_446

Multiple endocrine neoplasia type 2B MEN2B syndrome is caused by a missense mutation in the RET gene which replaces Met918 by Thr in the intracellular kinase domain of the protein This single amino acid substitution transforms the receptor into a constitutively active monomeric kinase RET(Men2B and produces an autosomal dominant syndrome characterized by medullary thyroid carcinoma pheochromocytomas musculoskeletal anomalies and mucosal ganglioneuromas The ligand GDNF stimulates RET activity through a co-receptor GFR alpha-1 In vitro studies have shown that the kinase and mitogenic properties of RET(Men2B are enhanced by GDNF/GFR alpha-1 stimulation A relevant clinical question is whether ablation of either GDNF or GFR alpha-1 could alter penetrance or severity of the MEN2B syndrome We report that ganglioneuromatous tumors caused by a RET(Men2B transgene in mice are not affected grossly or microscopically by the absence of gdnf or gfr alpha-1 Loss-of-function mutations in ret gdnf or gfr alpha-1 cause pan-intestinal aganglionosis in mice We find that expression of the RET(Men2B transgene in enteric neural progenitors after they colonize the gut does not prevent intestinal aganglionosis associated with gdnf or gfr alpha-1 deficiency