کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2121317 1085776 2015 15 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
DYRK1A-mediated Cyclin D1 Degradation in Neural Stem Cells Contributes to the Neurogenic Cortical Defects in Down Syndrome
موضوعات مرتبط
علوم زیستی و بیوفناوری بیوشیمی، ژنتیک و زیست شناسی مولکولی تحقیقات سرطان
پیش نمایش صفحه اول مقاله
DYRK1A-mediated Cyclin D1 Degradation in Neural Stem Cells Contributes to the Neurogenic Cortical Defects in Down Syndrome
چکیده انگلیسی


• 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.

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.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: EBioMedicine - Volume 2, Issue 2, February 2015, Pages 120–134
نویسندگان
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