Abstract
To gain insight into melanoma pathogenesis, we characterized an insertional mouse mutant, TG3, that is predisposed to develop multiple melanomas1,2. Physical mapping identified multiple tandem insertions of the transgene into intron 3 of Grm1 (encoding metabotropic glutamate receptor 1) with concomitant deletion of 70 kb of intronic sequence. To assess whether this insertional mutagenesis event results in alteration of transcriptional regulation, we analyzed Grm1 and two flanking genes for aberrant expression in melanomas from TG3 mice. We observed aberrant expression of only Grm1. Although we did not detect its expression in normal mouse melanocytes, Grm1 was ectopically expressed in the melanomas from TG3 mice. To confirm the involvement of Grm1 in melanocytic neoplasia, we created an additional transgenic line with Grm1 expression driven by the dopachrome tautomerase promoter. Similar to the original TG3, the Tg(Grm1)EPv line was susceptible to melanoma. In contrast to human melanoma, these transgenic mice had a generalized hyperproliferation of melanocytes with limited transformation to fully malignant metastasis. We detected expression of GRM1 in a number of human melanoma biopsies and cell lines but not in benign nevi and melanocytes. This study provides compelling evidence for the importance of metabotropic glutamate signaling in melanocytic neoplasia.
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Acknowledgements
We thank I. Jackson and G. Merlino for the Dct expression construct; V. Hearing for the Tyrp1 antibody; L. White for human melanocytes; J. Welch, M. Galdzicki and E. Eddings for technical help; and A. Weereratna, K. Sweder, L. Wise, R. Zhou and members of W.J.P.'s laboratory for helpful discussions. This work was supported by a Collaborative Research Award from the Cancer Institute of New Jersey (S.C. and J.G.), The Ohl Cancer Foundation (S.C.), New Jersey Commission on Cancer Research (S.C.), National Cancer Institute (S.C.) and National Institute of Environmental Health Sciences (S.C. and K.R.R.). P.M.P. was supported by an Australian National Health and Medical Research Council CJ Martin postdoctoral fellowship. K.C.-S. was supported by a fellowship from La Fondation Pour la Recherche Médicale.
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Pollock, P., Cohen-Solal, K., Sood, R. et al. Melanoma mouse model implicates metabotropic glutamate signaling in melanocytic neoplasia. Nat Genet 34, 108–112 (2003). https://doi.org/10.1038/ng1148
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DOI: https://doi.org/10.1038/ng1148
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