ArticleAmerican journal of human genetics2008
DYRK1A-dosage imbalance perturbs NRSF/REST levels, deregulating pluripotency and embryonic stem cell fate in Down syndrome.
Article in American journal of human genetics, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 85 papers, 1 of them a synthesis that pooled it.
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Who cites it
85 citing papers in PubMed, 1 synthesis or guideline pooled it, 155 citations in OpenAlex.
- Meta-analysis of heterogeneous Down Syndrome data reveals consistent genome-wide dosage effects related to neurological processes.BMC genomics · 2011Pooled it
- Discovery of a DNA methylation episignature for Weiss-Kruszka syndrome.Human genetics · 2026Article
- Sex-specific developmental phenotypes and their response to neonatalbioRxiv : the preprint server for biology · 2026Article
- DYRK1A and Parkinson's disease, facts and hypotheses.Neurobiology of disease · 2026Review
- Abnormal neuronal and synaptic morphology in Down syndrome brains reproduces in human isogenic cellular models.Cell death & disease · 2026Article
- Review
- The Dynamic Roles of Repressor Element 1-Silencing Transcription Factor (REST): A Double-Edged Sword in Neural Health and Disease.Molecular neurobiology · 2025Review
- Epigenetic links between paternal age, reproduction, and offspring health: a focus on sncRNAs.Reproduction & fertility · 2025Review
- DNMT3b-mediated CpA methylation facilitates REST binding and gene silencing and exacerbates hippocampal demyelination in diabetic mice.The Journal of biological chemistry · 2025Article
- Dysregulation of REST and its target genes impacts the fate of neural progenitor cells in down syndrome.Scientific reports · 2025Article
- Total cell N-glycosylation is altered during differentiation of induced pluripotent stem cells to neural stem cells and is disturbed by trisomy 21.BBA advances · 2025Article
- Sex-specific developmental alterations in DYRK1A expression in the brain of a Down syndrome mouse model.Neurobiology of disease · 2024Article
- REST Is Not Resting: REST/NRSF in Health and Disease.Biomolecules · 2023Review
- Functions of SRPK, CLK and DYRK kinases in stem cells, development, and human developmental disorders.FEBS letters · 2023Review
- REST in the Road Map of Brain Development.Cellular and molecular neurobiology · 2023Review
- REST Targets JAK-STAT and HIF-1 Signaling Pathways in Human Down Syndrome Brain and Neural Cells.International journal of molecular sciences · 2023Article
- New insights into the roles for DYRK family in mammalian development and congenital diseases.Genes & diseases · 2023Review
- Cell models for Down syndrome-Alzheimer's disease research.Neuronal signaling · 2022Review
- The chromosome 21 kinase DYRK1A: emerging roles in cancer biology and potential as a therapeutic target.Oncogene · 2022Review
- A reassessment of Jackson's checklist and identification of two Down syndrome sub-phenotypes.Scientific reports · 2022Article
25 more citing papers are in PubMed but not listed here.
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Authors and funding
24 authors at 8 institutions in 5 countries.
Funding
Abstract
Down syndrome (DS) is the most common cause of mental retardation. Many neural phenotypes are shared between DS individuals and DS mouse models; however, the common underlying molecular pathogenetic mechanisms remain unclear. Using a transchromosomic model of DS, we show that a 30%-60% reduced expression of Nrsf/Rest (a key regulator of pluripotency and neuronal differentiation) is an alteration that persists in trisomy 21 from undifferentiated embryonic stem (ES) cells to adult brain and is reproducible across several DS models. Using partially trisomic ES cells, we map this effect to a three-gene segment of HSA21, containing DYRK1A. We independently identify the same locus as the most significant eQTL controlling REST expression in the human genome. We show that specifically silencing the third copy of DYRK1A rescues Rest levels, and we demonstrate altered Rest expression in response to inhibition of DYRK1A expression or kinase activity, and in a transgenic Dyrk1A mouse. We reveal that undifferentiated trisomy 21 ES cells show DYRK1A-dose-sensitive reductions in levels of some pluripotency regulators, causing premature expression of transcription factors driving early endodermal and mesodermal differentiation, partially overlapping recently reported downstream effects of Rest +/-. They produce embryoid bodies with elevated levels of the primitive endoderm progenitor marker Gata4 and a strongly reduced neuroectodermal progenitor compartment. Our results suggest that DYRK1A-mediated deregulation of REST is a very early pathological consequence of trisomy 21 with potential to disturb the development of all embryonic lineages, warranting closer research into its contribution to DS pathology and new rationales for therapeutic approaches.
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