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.
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Trisomic DYRK1A has been linked to aberrant brain development, brain pathology, and impaired cognitive phenotypes in individuals with DS and DS mouse models.
“Trisomic DYRK1A has been linked to aberrant brain development, brain pathology, and impaired cognitive phenotypes in individuals with DS and DS mouse models (Arron et al., 2006; Becker et al., 2014; Dowjat et al., 2007; Duchon and Herault, 2016; Liu et al., 2008).”
From Sex-specific developmental alterations in DYRK1A expression in the brain of a Down syndrome mouse model (2024) · cites this paper as Arron et al., 2006
DYRK1A is a serine-threonine kinase that utilizes autophosphorylation to enhance activity and stabilize itself, regulates many downstream proteins and transcription factors, and has a crucial role during brain development.
“DYRK1A is a serine-threonine kinase that utilizes autophosphorylation to enhance activity and stabilize itself, regulates many downstream proteins and transcription factors, and has a crucial role during brain development (Ahn et al., 2006; Arron et al., 2006; Atas-Ozcan et al., 2021; Branchi et al., 2004; Canzonetta et al., 2008; Hammerle et al., 2011; Martinez de Lagran et al., 2004; Park and Ch”
From Sex-specific developmental alterations in DYRK1A expression in the brain of a Down syndrome mouse model (2024) · cites this paper as Arron et al., 2006
The substrates regulated by DYRK1A phosphorylation are located in both the nucleus and cytosol, and this regulation is likely to be tissue- and time-specific.
“The substrates regulated by DYRK1A phosphorylation are located in both the nucleus and cytosol, and this regulation is likely to be tissue and time-specific (Arron et al., 2006; Chen-Hwang et al., 2002; de Graaf et al., 2004; Kaczmarski et al., 2014; Marti et al., 2003; Woods et al., 2001).”
From Sex-specific developmental alterations in DYRK1A expression in the brain of a Down syndrome mouse model (2024) · cites this paper as Arron et al., 2006
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- Authors
- 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.
- Affiliations
- Stanford Medicine (US)
- Kyoto University (JP)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Graef, Isabella A.
- Crabtree, Gerald R.
- ORCID
- Venue
- Nature
- Published
- 2006-03-22
- Volume
- 441
- Issue
- 7093
- Pages
- 595-600
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2042916026
- Cited by
- 698
- References
- 1
- Citations by year
- 2026: 14 · 2025: 10 · 2024: 20 · 2023: 27 · 2022: 31 · 2021: 29 · 2020: 25 · 2019: 23 · 2018: 33 · 2017: 29 · 2016: 28 · 2015: 33 · 2014: 36 · 2013: 46 · 2012: 46
- FWCI
- 56.60
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- Down syndrome, DSCR1, DYRK1A, NFAT transcription factors, calcineurin, gene dosage, transcriptional autoregulation, vertebrate development, mouse models of Down syndrome
- MeSH terms
- Dyrk Kinases, Animals, Calcium-Binding Proteins, Chromosomes, Human, Pair 21, Disease Models, Animal, Down Syndrome, Gene Expression Regulation, Humans, Mice, Transgenic, Models, Genetic, Muscle Proteins, Mutation, Phenotype, Protein-Tyrosine Kinases, Protein Serine-Threonine Kinases, Gene Dosage, Transgenes, Chromosomes, Mammalian, Intracellular Signaling Peptides and Proteins, NFATC Transcription Factors, Mice
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