I. Rajan et al., RETMen2B-transgene produces sympathoadrenal tumors but does not prevent intestinal aganglionosis in gdnf-/- or gfr alpha-1-/- mice, PEDIATR D P, 4(5), 2001, pp. 446-453
Multiple endocrine neoplasia type 2B (MEN2B) syndrome is caused by a missen
se mutation in the RET gene, which replaces Met918 by Thr in the intracellu
lar kinase domain of the protein. This single amino acid substitution trans
forms the receptor into a constitutively active monomeric kinase (RETMen2B)
and produces an autosomal dominant syndrome characterized by medullary thy
roid carcinoma, pheochromocytomas, musculoskeletal anomalies, and mucosal g
anglioneuromas. The ligand, GDNF, stimulates RET activity through a corecep
tor, GFR alpha -1. In vitro studies have shown that the kinase and mitogeni
c properties of RETMen2B are enhanced by GDNF/GFR alpha -1 stimulation. A r
elevant 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 RETMen2B transgene in mice are not af
fected grossly or microscopically by the absence of gdnf or gfr alpha -1. L
oss-of-function mutations in ret, gdnf, or gfr alpha -1 cause pan-intestina
l aganglionosis in mice. We find that expression of the RETMen2B transgene
in enteric neural progenitors, after they colonize the gut, does not preven
t intestinal aganglionosis associated with gdnf or gfr alpha -1 deficiency.