NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21

Joseph R. Arron, Monte M. Winslow, Alberto Polleri, Ching Pin Chang, Hai Wu, Xin Gao, Joel R. Neilson, Lei Chen, Jeremy J. Heit, Seung K. Kim, Nobuyuki Yamasaki, Tsuyoshi Miyakawa, Uta Francke, Isabella A. Graef, Gerald R. Crabtree

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469 Scopus citations

Abstract

Trisomy 21 results in Down's syndrome, but little is known about how a 1.5-fold increase in gene dosage produces the pleiotropic phenotypes of Down's syndrome. Here we report that two genes, DSCR1 and DYRK1A , lie within the critical region of human chromosome 21 and act synergistically to prevent nuclear occupancy of NFATc transcription factors, which are regulators of vertebrate development. We use mathematical modelling to predict that autoregulation within the pathway accentuates the effects of trisomy of DSCR1 and DYRK1A, leading to failure to activate NFATc target genes under specific conditions. Our observations of calcineurin-and Nfatc-deficient mice, Dscr1- and Dyrk1a-overexpressing mice, mouse models of Down's syndrome and human trisomy 21 are consistent with these predictions. We suggest that the 1.5-fold increase in dosage of DSCR1 and DYRK1A cooperatively destabilizes a regulatory circuit, leading to reduced NFATc activity and many of the features of Down's syndrome. More generally, these observations suggest that the destabilization of regulatory circuits can underlie human disease.

Original languageEnglish (US)
Pages (from-to)595-600
Number of pages6
JournalNature
Volume441
Issue number7093
DOIs
StatePublished - Jun 1 2006

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    Arron, J. R., Winslow, M. M., Polleri, A., Chang, C. P., Wu, H., Gao, X., Neilson, J. R., Chen, L., Heit, J. J., Kim, S. K., Yamasaki, N., Miyakawa, T., Francke, U., Graef, I. A., & Crabtree, G. R. (2006). NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21. Nature, 441(7093), 595-600. https://doi.org/10.1038/nature04678