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NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21
Joseph R Arron1, Monte M Winslow, Alberto Polleri
1Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, USA.
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.
Insights
Down's syndrome, caused by Trisomy 21, involves gene dosage effects. Increased DSCR1 and DYRK1A dosage disrupts NFATc regulation, causing developmental issues and disease features.
Area of Science:
- Genetics
- Developmental Biology
- Molecular Biology
Background:
- Down's syndrome (Trisomy 21) presents complex phenotypes, but the precise mechanisms linking gene dosage to these effects remain unclear.
- Understanding the role of specific genes on chromosome 21 is crucial for elucidating Down's syndrome pathogenesis.
- Nuclear occupancy of NFATc transcription factors is vital for vertebrate development.
Purpose of the Study:
- To investigate how increased gene dosage of DSCR1 and DYRK1A on chromosome 21 contributes to Down's syndrome phenotypes.
- To elucidate the synergistic interaction between DSCR1 and DYRK1A in regulating NFATc transcription factors.
- To explore the impact of trisomy on regulatory circuits and its implications for human diseases.
Main Methods:
- Mathematical modeling to predict pathway dynamics under trisomic conditions.
- Analysis of gene expression and protein activity in various mouse models (gene-deficient, gene-overexpressing, Down's syndrome models).
- Comparison of findings with human Trisomy 21 data.
Main Results:
- DSCR1 and DYRK1A, located in the critical region of chromosome 21, act synergistically to inhibit NFATc nuclear localization.
- Mathematical modeling predicted that trisomy of DSCR1 and DYRK1A accentuates pathway effects, impairing NFATc target gene activation.
- Experimental data from mouse models and human Trisomy 21 samples corroborated the model's predictions, showing reduced NFATc activity.
Conclusions:
- A 1.5-fold increase in DSCR1 and DYRK1A dosage cooperatively destabilizes a key regulatory circuit.
- This destabilization leads to reduced NFATc activity, contributing to multiple features of Down's syndrome.
- Destabilization of regulatory circuits is a potential mechanism underlying various human diseases.
