title: RET(Men2B)-transgene produces sympathoadrenal tumors but does not prevent intestinal aganglionosis in gdnf-/- or gfr alpha-1(-/-) mice.
abstract: 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.
authors.affiliation: Department of Pathology, University of Washington, Seattle 98195, USA.
authors.forename: I
authors.initials: I
authors.lastname: Rajan
authors.forename: C
authors.initials: C
authors.lastname: Gestblom
authors.forename: R P
authors.initials: RP
authors.lastname: Kapur
mesh_terms: D000110:Acetylcholinesterase / Q000032:analysis; D000310:Adrenal Gland Neoplasms / Q000235:genetics* / Q000473:pathology; D000818:Animals; D000831:Animals, Newborn; D002447:Celiac Plexus / Q000473:pathology; D003106:Colon / Q000294:innervation; D004247:DNA / Q000032:analysis; D004195:Disease Models, Animal; D029721:Drosophila Proteins; D005260:Female; D005729:Ganglioneuroma / Q000235:genetics* / Q000473:pathology; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D006627:Hirschsprung Disease / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control; D007091:Image Processing, Computer-Assisted; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018814:Multiple Endocrine Neoplasia Type 2b / Q000235:genetics*; D009197:Myenteric Plexus / Q000201:enzymology / Q000473:pathology; D016133:Polymerase Chain Reaction; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics*; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases / Q000172:deficiency / Q000235:genetics*
chemical_list: D029721:Drosophila Proteins; C494988:Gfra1 protein, mouse; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D011518:Proto-Oncogene Proteins; D004247:DNA; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila; C494999:Ret protein, mouse; D000110:Acetylcholinesterase