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Cited by 93Neurogenesis and neuroplasticity mechanismsDown syndrome and intellectual disability researchGenetics and Neurodevelopmental Disorders

DYRK1A-mediated cyclin D1 degradation in neural stem cells contributes to the neurogenic cortical defects in down syndrome

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Najas, Sònia, Arranz, Juan, Lochhead, Pamela A., Ashford, Anne L., Oxley, David, Delabar, Jean M., Cook, Simon J., Barallobre, María José +1 more·2015·EBioMedicine
DOI 10.1016/j.ebiom.2015.01.010PMC PMC4484814
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Abstract

Alterations in cerebral cortex connectivity lead to intellectual disability and in Down syndrome, this is associated with a deficit in cortical neurons that arises during prenatal development. However, the pathogenic mechanisms that cause this deficit have not yet been defined. Here we show that the human DYRK1A kinase on chromosome 21 tightly regulates the nuclear levels of Cyclin D1 in embryonic cortical stem (radial glia) cells, and that a modest increase in DYRK1A protein in transgenic embryos lengthens the G1 phase in these progenitors. These alterations promote asymmetric proliferative divisions at the expense of neurogenic divisions, producing a deficit in cortical projection neurons that persists in postnatal stages. Moreover, radial glial progenitors in the Ts65Dn mouse model of Down syndrome have less Cyclin D1, and Dyrk1a is the triplicated gene that causes both early cortical neurogenic defects and decreased nuclear Cyclin D1 levels in this model. These data provide insights into the mechanisms that couple cell cycle regulation and neuron production in cortical neural stem cells, emphasizing that the deleterious effect of DYRK1A triplication in the formation of the cerebral cortex begins at the onset of neurogenesis, which is relevant to the search for early therapeutic interventions in Down syndrome.

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  • Overexpression of DYRK1A/Dyrk1a both in vivo and in vitro results in the nuclear export of Cyclin D1, reducing Cyclin D1 protein levels at multiple developmental ages in TgDyrk1a mice (E11.5 and E14.5).

    “Overexpression of DYRK1A/Dyrk1a both in vivo and in vitro results in the nuclear export of Cyclin D1, resulting in reductions in Cyclin D1 protein levels at multiple developmental ages in TgDyrk1a mice (E11.5 & E14.5) (Najas et al., 2015; Park et al., 2010; Soppa et al., 2014; Yabut et al., 2010).”

    From Sex-specific developmental alterations in DYRK1A expression in the brain of a Down syndrome mouse model (2024) · cites this paper as Najas et al., 2015

    The Results section reports reduced Cyclin D1 protein and nuclear Cyclin D1 in E11.5 TgDyrk1a embryos, and reduced nuclear Cyclin D1 at E13.5—not the claimed E14.5. It demonstrates DYRK1A-mediated Cyclin D1 phosphorylation in vitro, but treats nuclear export in cultured cells as a previously reported finding and infers, rather than directly observes, the mechanism in embryos. Page numbers are unavailable in our copy. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • DYRK1A can phosphorylate and possibly regulate Cyclin D1 (G1-to-S phase transition and cell proliferation) and p27 (neuronal differentiation and cell cycle exit).

    “This mechanism of action could be attributed to the ability of DYRK1A to phosphorylate and possibly regulate Cyclin D1 (G1-to-S phase transition and cell proliferation) and p27 (neuronal differentiation and cell cycle exit) (Frank and Tsai, 2009; Hindley and Philpott, 2012; Najas et al., 2015; Tejedor and Hammerle, 2011).”

    From Sex-specific developmental alterations in DYRK1A expression in the brain of a Down syndrome mouse model (2024) · cites this paper as Najas et al., 2015

    The Results show that DYRK1A phosphorylates Cyclin D1 at T286 and links reduced Cyclin D1 to altered cell-cycle progression in neural progenitors (page unavailable). The Discussion mentions reports of increased p27 levels in cell culture, but does not show DYRK1A phosphorylating p27; it found no p27 change in the embryos studied and identifies Cyclin D1, not p27, as the likely mediator. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • DYRK1A/Dyrk1a overexpression results in more cells in the G1/0 phase versus S or G2/M phase, leading to cell proliferation deficits, premature cell exit and differentiation, and the nuclear export of Cyclin D1.

    “In addition, DYRK1A/Dyrk1a overexpression results in more cells in the G1/0 phase versus S or G2/M phase, leading to cell proliferation deficits, premature cell exit and differentiation, and the nuclear export of Cyclin D1 (Najas et al., 2015; Soppa et al., 2014).”

    From Sex-specific developmental alterations in DYRK1A expression in the brain of a Down syndrome mouse model (2024) · cites this paper as Najas et al., 2015

    The Results (page unavailable) show that DYRK1A-overexpressing mouse radial-glial progenitors have longer G1 and S phases and reduced nuclear Cyclin D1. They do not show that a larger fraction of cells is in G1/G0 rather than S or G2/M, or directly demonstrate Cyclin D1 export in these embryos. The reported premature cell exit and differentiation are not supported: the Results report similar cell-cycle exit rates at E14.5 and fewer differentiating neurons early in neurogenesis. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Ts65Dn E11.5 embryos contain 1.5-fold more DYRK1A protein and display significant decreases in Cyclin D1 levels.

    “Ts65Dn E11.5 embryos contain 1.5-fold more DYRK1A protein and display significant decreases in Cyclin D1 levels.”

    From Sex-specific developmental alterations in DYRK1A expression in the brain of a Down syndrome mouse model (2024) · cites this paper as Najas et al., 2015

  • Normalization of Dyrk1a copy number restored levels of Cyclin D1, the number of intermediate progenitors, and the production of neurons at multiple developmental time points.

    “Normalization of Dyrk1a copy number restored levels of Cyclin D1, the number of intermediate progenitors, as well as the production of neurons at multiple developmental time points (Najas et al., 2015).”

    From Sex-specific developmental alterations in DYRK1A expression in the brain of a Down syndrome mouse model (2024) · cites this paper as Najas et al., 2015

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Authors
Najas, S., Arranz, J., Lochhead, P. A., Ashford, A. L., Oxley, D., Delabar, J. M., Cook, S. J., Barallobre, M. J., & Arbonés, M. L.
Affiliations
  • Consejo Superior de Investigaciones Científicas (ES)
  • Babraham Institute (GB)
  • Centre National de la Recherche Scientifique (FR)
Corresponding author
Arbonés, Maria L.
ORCID
Venue
EBioMedicine
Publisher
Elsevier BV
Published
2015-02
Volume
2
Issue
2
Pages
120-134
ISSN
2352-3964 (ISSN-L)
DOI
10.1016/j.ebiom.2015.01.010
PMC
PMC4484814
OpenAlex
W2141621273
Cited by
92
References
88
Citations by year
2026: 16 · 2025: 7 · 2024: 8 · 2023: 11 · 2022: 9 · 2021: 7 · 2020: 4 · 2019: 8 · 2018: 5 · 2017: 7 · 2016: 7 · 2015: 3
FWCI
2.97
Type
journal article
Language
en
Open access
Licence
Locations
  • EBioMedicine (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Spanish Ministry of Economy and Competitiveness (MINECO) (SAF-2010-17004, SAF2013-46676-P, CSIC-201020I003)
  • Jérôme Lejeune Foundation
  • Generalitat de Catalunya (2009SGR1464)
  • FI fellowship from the Generalitat de Catalunya (2011B1-OG242)
  • FPU fellowship from the MINECO (AP2012-3064)
  • JAE DOC-CSIC/European Social Fund (BES2011-047472)
  • Biotechnology and Biological Sciences Research Council (BBSRC)
  • Association for International Cancer Research
Topics
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Keywords
DYRK1A, cyclin D1, Down syndrome, radial glial progenitors, neural stem cells, cortical neurogenesis, Ts65Dn mouse model, G1 phase, asymmetric cell division, cortical projection neurons, intellectual disability, cortical development
MeSH terms
Dyrk Kinases, Animals, Cerebral Cortex, Disease Models, Animal, Down Syndrome, Humans, Mice, Inbred C57BL, Mice, Transgenic, Protein-Tyrosine Kinases, Telencephalon, Trisomy, G1 Phase, Protein Serine-Threonine Kinases, Gene Dosage, Cyclin D1, Mice, Neurogenesis, Neural Stem Cells

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