DYRK1A-mediated Cyclin D1 Degradation in Neural Stem Cells Contributes to the Neurogenic Cortical Defects in Down Syndrome.
DYRK1A-mediated Cyclin D1 Degradation in Neural Stem Cells Contributes to the Neurogenic Cortical Defects in Down Syndrome.
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DOI：
10.1016/j.ebiom.2015.01.010
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发表时间：
2015
期刊：
影响因子：
11.1
通讯作者：
Arbones, Maria L.
中科院分区：
文献类型：
--
作者：
Najas, Sonia;Arranz, Juan;Lochhead, Pamela A.;Ashford, Anne L.;Oxley, David;Delabar, Jeanm.;Cook, Simon J.;Jose Barallobre, Maria;Arbones, Maria L.
关键词：
大脑皮层连接的改变导致智力残疾，在唐氏综合症中，这与产前发育期间出现的皮层神经元缺陷有关。然而，导致这种缺陷的致病机制尚未确定。在这里，我们表明21号染色体上的人类DYRK 1A激酶严格调节胚胎皮质干（放射状胶质细胞）细胞中细胞周期蛋白D1的核水平，并且转基因胚胎中DYRK 1A蛋白的适度增加会延长这些祖细胞的G1期。这些改变促进不对称的增殖分裂的神经原性部门的费用，产生的赤字皮质投射神经元，持续在出生后的阶段。此外，在唐氏综合征Ts65Dn小鼠模型中，放射状胶质祖细胞具有较少的细胞周期蛋白D1，Dyrk1a是在该模型中导致早期皮质神经源性缺陷和细胞核细胞周期蛋白D1水平降低的三重基因。这些数据提供了深入了解的机制，耦合细胞周期调控和皮层神经干细胞中的神经元产生，强调DYRK1A三倍体在大脑皮层的形成中的有害影响开始于神经发生的发病，这是相关的唐氏综合征的早期治疗干预措施的搜索。激酶DYRK1A调节发育中的大脑皮层祖细胞中的细胞周期蛋白D1水平和细胞周期持续时间。DYRK1A基因剂量失衡改变了神经发生开始时皮质祖细胞的神经输出。Dyrk1a基因剂量的正常化恢复了唐氏综合征三体小鼠模型的早期皮质神经发生
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. Kinase DYRK1A regulates Cyclin D1 levels and cell cycle duration in progenitors of the developing cerebral cortex. DYRK1A gene-dosage imbalance alters the neurogenic output of cortical progenitors at the onset of neurogenesis. Normalization of Dyrk1a gene-dosage restores early cortical neurogenesis in a trisomic mouse model for Down syndrome.
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