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 language | English |
|---|---|
| Pages (from-to) | 595-600 |
| Number of pages | 6 |
| Journal | Nature |
| Volume | 441 |
| Issue number | 7093 |
| DOIs | |
| Publication status | Published - 01-06-2006 |
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All Science Journal Classification (ASJC) codes
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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 journal › Article
TY - JOUR
T1 - NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21
AU - Arron, Joseph R.
AU - Winslow, Monte M.
AU - Polleri, Alberto
AU - Chang, Ching Pin
AU - Wu, Hai
AU - Gao, Xin
AU - Neilson, Joel R.
AU - Chen, Lei
AU - Heit, Jeremy J.
AU - Kim, Seung K.
AU - Yamasaki, Nobuyuki
AU - Miyakawa, Tsuyoshi
AU - Francke, Uta
AU - Graef, Isabella A.
AU - Crabtree, Gerald R.
PY - 2006/6/1
Y1 - 2006/6/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=33646171446&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33646171446&partnerID=8YFLogxK
U2 - 10.1038/nature04678
DO - 10.1038/nature04678
M3 - Article
C2 - 16554754
AN - SCOPUS:33646171446
VL - 441
SP - 595
EP - 600
JO - Nature
JF - Nature
SN - 0028-0836
IS - 7093
ER -