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

Research output: Contribution to journalArticle

450 Citations (Scopus)

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
Externally publishedYes

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Chromosomes, Human, Pair 21
Down Syndrome
Gene Dosage
Calcineurin
Trisomy
Human Chromosomes
Genes
Vertebrates
Homeostasis
Transcription Factors
Phenotype

ASJC Scopus subject areas

  • General

Cite this

Arron, J. R., Winslow, M. M., Polleri, A., Chang, C-P., Wu, H., Gao, X., ... 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

NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21. / Arron, Joseph R.; Winslow, Monte M.; Polleri, Alberto; Chang, Ching-Pin; Wu, Hai; Gao, Xin; Neilson, Joel R.; Chen, Lei; Heit, Jeremy J.; Kim, Seung K.; Yamasaki, Nobuyuki; Miyakawa, Tsuyoshi; Francke, Uta; Graef, Isabella A.; Crabtree, Gerald R.

In: Nature, Vol. 441, No. 7093, 01.06.2006, p. 595-600.

Research output: Contribution to journalArticle

Arron, JR, Winslow, MM, Polleri, A, Chang, C-P, Wu, H, Gao, X, Neilson, JR, Chen, L, Heit, JJ, Kim, SK, Yamasaki, N, Miyakawa, T, Francke, U, Graef, IA & Crabtree, GR 2006, 'NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21', Nature, vol. 441, no. 7093, pp. 595-600. https://doi.org/10.1038/nature04678
Arron JR, Winslow MM, Polleri A, Chang C-P, Wu H, Gao X et al. NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21. Nature. 2006 Jun 1;441(7093):595-600. https://doi.org/10.1038/nature04678
Arron, Joseph R. ; Winslow, Monte M. ; Polleri, Alberto ; Chang, Ching-Pin ; Wu, Hai ; Gao, Xin ; Neilson, Joel R. ; Chen, Lei ; Heit, Jeremy J. ; Kim, Seung K. ; Yamasaki, Nobuyuki ; Miyakawa, Tsuyoshi ; Francke, Uta ; Graef, Isabella A. ; Crabtree, Gerald R. / NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21. In: Nature. 2006 ; Vol. 441, No. 7093. pp. 595-600.
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