期刊
EBIOMEDICINE
卷 2, 期 2, 页码 120-134出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ebiom.2015.01.010
关键词
Cell cycle regulation; DYRK kinases; Cerebral cortex development; Trisomy 21; Neurodevelopmental disorders; Intellectual disability
资金
- Spanish Ministry of Economy and Competitiveness (MINECO) [SAF-2010-17004, SAF2013-46676-P, CSIC-201020I003]
- Jerome Lejeune Foundation
- Generalitat de Catalunya [2009SGR1464]
- FI fellowship from the Generalitat de Catalunya [2011B1-OG242]
- FPU fellowship from the MINECO [AP2012-3064]
- program JAE DOC-CSIC/European Social Fund
- FPI fellowship from the MINECO [BES2011-047472]
- Biotechnology and Biological Sciences Research Council (BBSRC)
- BBSRC CASE
- AstraZeneca
- Association for International Cancer Research
- BBSRC [BB/L008793/1, BBS/E/B/000C0417] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BBS/E/B/0000C199, BBS/E/B/000C0417, BB/L008793/1] Funding Source: researchfish
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. (C) 2015 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
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