Ganglioneuromas and renal anomalies are induced by activated RET(MEN2B) in transgenic mice
D A Sweetser1, G J Froelick, A M Matsumoto
1Pediatric Oncology, Fred Hutchinson Cancer Research Center, Seattle, Washington 98105, USA.
Abstract:
Multiple endocrine neoplasia type 2B (MEN2B) is an autosomal dominant syndrome characterized by the development of medullary thyroid carcinoma, pheochromocytomas, musculoskeletal anomalies and mucosal ganglioneuromas. MEN2B is caused by a specific mutation (Met918-->Thr) in the RET receptor tyrosine kinase. Different mutations of RET lead to other conditions including MEN2A, familial medullary thyroid carcinoma and intestinal aganglionosis (Hirschsprung disease). Transgenic mice were created using the dopamine beta-hydroxylase promoter to direct expression of RET(MEN2B) in the developing sympathetic and enteric nervous systems and the adrenal medulla. DbetaH-RET(MEN2B) transgenic mice developed benign neuroglial tumors, histologically identical to human ganglioneuromas, in their sympathetic nervous systems and adrenal glands. The enteric nervous system was not affected. The neoplasms in DbetaH-RET(MEN2B) mice were similar to benign neuroglial tumors induced in transgenic mice by activated Ras expression under control of the same promoter. Levels of phosphorylated MAP kinase were not increased in the RET(MEN2B)-induced neurolglial proliferations, suggesting that alternative pathways may play a role in the pathogenesis of these lesions. Transgenic mice with the highest levels of DbetaH-RET(MEN2B) expression, unexpectedly developed renal malformations analogous to those reported with loss of function mutations in the Ret gene.
Insights
Multiple endocrine neoplasia type 2B (MEN2B) is linked to RET receptor tyrosine kinase mutations. This study created transgenic mice modeling MEN2B, revealing neuroglial tumors and unexpected renal malformations.
Area of Science:
- Genetics
- Oncology
- Developmental Biology
Background:
- Multiple endocrine neoplasia type 2B (MEN2B) is an autosomal dominant disorder.
- MEN2B is caused by a specific mutation (Met918-->Thr) in the RET receptor tyrosine kinase, leading to medullary thyroid carcinoma, pheochromocytomas, and ganglioneuromas.
- Other RET gene mutations cause MEN2A, familial medullary thyroid carcinoma, and Hirschsprung disease.
Purpose of the Study:
- To create a mouse model for MEN2B using a dopamine beta-hydroxylase promoter to express RET(MEN2B).
- To investigate the development of tumors and other abnormalities in the sympathetic nervous system, enteric nervous system, and adrenal medulla.
Main Methods:
- Generation of DbetaH-RET(MEN2B) transgenic mice.
- Histological analysis of tumors and tissues.
- Assessment of signaling pathways, including MAP kinase phosphorylation.
Main Results:
- DbetaH-RET(MEN2B) mice developed benign neuroglial tumors in the sympathetic nervous system and adrenal glands, similar to human ganglioneuromas.
- The enteric nervous system was unaffected.
- Unexpectedly, high expression levels of DbetaH-RET(MEN2B) led to renal malformations analogous to those seen in Ret loss-of-function mutations.
- Phosphorylated MAP kinase levels were not elevated in the RET(MEN2B)-induced tumors, suggesting alternative pathogenic pathways.
Conclusions:
- The DbetaH-RET(MEN2B) mouse model recapitulates key features of MEN2B, including neuroglial tumor formation.
- The study highlights a potential role for alternative signaling pathways in MEN2B pathogenesis.
- The unexpected development of renal malformations suggests a complex interplay between RET signaling and kidney development, potentially involving both gain-of-function and loss-of-function effects.
More Related Videos
09:37Defining Gene Functions in Tumorigenesis by Ex vivo Ablation of Floxed Alleles in Malignant Peripheral Nerve Sheath Tumor Cells
Published on: August 25, 2021
08:57Identifying, Diagnosing, and Grading Malignant Peripheral Nerve Sheath Tumors in Genetically Engineered Mouse Models
Published on: May 17, 2024
