@article{0ba568c2a8fe4970bbda7a3de8981807,
title = "NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21",
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.",
author = "Arron, {Joseph R.} and Winslow, {Monte M.} and Alberto Polleri and Chang, {Ching Pin} and Hai Wu and Xin Gao and Neilson, {Joel R.} and Lei Chen and Heit, {Jeremy J.} and Kim, {Seung K.} and Nobuyuki Yamasaki and Tsuyoshi Miyakawa and Uta Francke and Graef, {Isabella A.} and Crabtree, {Gerald R.}",
note = "Funding Information: Acknowledgements We thank S. L. Schreiber, W. Mobley and K. Tanda for discussion and comments on the manuscript; W. Becker for Dyrk1a expression constructs; E. Olson for the anti-DCSR1 (MCIP1) antibody; R. S. Williams for the Dscr1 (MCIP1) expression construct; K. Stankunas, G. Krampitz and C. Shang for help with histology on Dyrk1a and Dscr1 transgenic mice; E. Wang for mass spectrometric analysis; W. Mobley and K. Zhan for providing Ts65Dn mice; and F. Wang, members of the Crabtree laboratory, J. Lee, M. Dionne and S. Arron for discussions. We thank the Stanford Center for Innovation in In Vivo Imaging (NCI Small Animal Imaging Resource Program Grant), the Stanford Imaging Facility and the Stanford Proteomics and Integrated Research Facility. These studies were supported by the Howard Hughes Medical Institute and NIH grants to G.R.C., and by the Christopher Reeve Paralysis Foundation (I.A.G.). M.M.W. is supported by a Stanford Graduate Fellowship and an HHMI predoctoral fellowship, C.-P.C. by grants from AHA and the NIH, J.R.A. by a postdoctoral fellowship from the Berry Foundation, J.J.H. and S.K.K. by the ADA, H.W. by a Damon Runyon Cancer Research Foundation postdoctoral fellowship and a Muscular Dystrophy Association research development grant, and T.M. by KAKENHI from JSPS and MEXT and by a grant from JST BIRD.",
year = "2006",
month = jun,
day = "1",
doi = "10.1038/nature04678",
language = "English",
volume = "441",
pages = "595--600",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7093",
}