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

Oncogene volume 18, pages 877–886 (1999)Cite this article

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 β-hydroxylase promoter to direct expression of RETMEN2B in the developing sympathetic and enteric nervous systems and the adrenal medulla. DβH-RETMEN2B 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 DβH-RETMEN2B mice were similar to benign neuroglial tumors induced in transgenic mice by activated Ras expression under control of the same promoter. Levels of phoshorylated MAP kinase were not increased in the RETMEN2B-induced neurolgial proliferations, suggesting that alternative pathways may play a role in the pathogenesis of these lesions. Transgenic mice with the highest levels of DβH-RETMEN2B expression, unexpectedly developed renal malformations analogous to those reported with loss of function mutations in the Ret gene.

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Acknowledgements

DAS is supported by NIH training grant in Pediatric Hematology and Oncology (T32CA09351). RPK is supported by NIH RO1DK52530. AMM received support from VA Medical Research funds and NIH grant HD12629. We thank Masahide Takahashi for the kind gift of a human c-ret cDNA clone.

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Authors and Affiliations

  1. Pediatric Oncology, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, C1-169, Seattle, 98105, Washington, USA

    David A Sweetser

  2. Department of Biochemistry/Howard Hughes Medical Institute, University of Washington Medical Center, Box 357370, Seattle, 98195, Washington, USA

    David A Sweetser, Glenda J Froelick, Kathy E Kafer & Richard D Palmiter

  3. Department of Pathology, University of Washington Medical Center, Box 357470, Seattle, 98195, Washington, USA

    Raj P Kapur

  4. Department of Medicine and Population Center for Research in Reproduction, University of Washington School of Medicine,

    Alvin M Matsumoto & Brett Marck

  5. the Geriatric Research, Education and Clinical Center, VA Puget Sound Health Care System, Seattle, 98108, Washington, USA

    Alvin M Matsumoto & Brett Marck

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  1. David A Sweetser
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Sweetser, D., Froelick, G., Matsumoto, A. et al. Ganglioneuromas and renal anomalies are induced by activated RETMEN2B in transgenic mice. Oncogene 18, 877–886 (1999). https://doi.org/10.1038/sj.onc.1202376

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