Cargando…

DYRK1A-mediated Cyclin D1 Degradation in Neural Stem Cells Contributes to the Neurogenic Cortical Defects in 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...

Descripción completa

Detalles Bibliográficos
Autores principales: Najas, Sònia, Arranz, Juan, Lochhead, Pamela A., Ashford, Anne L., Oxley, David, Delabar, Jean M., Cook, Simon J., Barallobre, María José, Arbonés, Maria L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4484814/
https://www.ncbi.nlm.nih.gov/pubmed/26137553
http://dx.doi.org/10.1016/j.ebiom.2015.01.010
_version_ 1782378714035650560
author Najas, Sònia
Arranz, Juan
Lochhead, Pamela A.
Ashford, Anne L.
Oxley, David
Delabar, Jean M.
Cook, Simon J.
Barallobre, María José
Arbonés, Maria L.
author_facet Najas, Sònia
Arranz, Juan
Lochhead, Pamela A.
Ashford, Anne L.
Oxley, David
Delabar, Jean M.
Cook, Simon J.
Barallobre, María José
Arbonés, Maria L.
author_sort Najas, Sònia
collection PubMed
description 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.
format Online
Article
Text
id pubmed-4484814
institution National Center for Biotechnology Information
language English
publishDate 2015
publisher Elsevier
record_format MEDLINE/PubMed
spelling pubmed-44848142015-07-01 DYRK1A-mediated Cyclin D1 Degradation in Neural Stem Cells Contributes to the Neurogenic Cortical Defects in Down Syndrome Najas, Sònia Arranz, Juan Lochhead, Pamela A. Ashford, Anne L. Oxley, David Delabar, Jean M. Cook, Simon J. Barallobre, María José Arbonés, Maria L. EBioMedicine Original Research Article 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. Elsevier 2015-01-17 /pmc/articles/PMC4484814/ /pubmed/26137553 http://dx.doi.org/10.1016/j.ebiom.2015.01.010 Text en © 2015 The Authors http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Original Research Article
Najas, Sònia
Arranz, Juan
Lochhead, Pamela A.
Ashford, Anne L.
Oxley, David
Delabar, Jean M.
Cook, Simon J.
Barallobre, María José
Arbonés, Maria L.
DYRK1A-mediated Cyclin D1 Degradation in Neural Stem Cells Contributes to the Neurogenic Cortical Defects in Down Syndrome
title DYRK1A-mediated Cyclin D1 Degradation in Neural Stem Cells Contributes to the Neurogenic Cortical Defects in Down Syndrome
title_full DYRK1A-mediated Cyclin D1 Degradation in Neural Stem Cells Contributes to the Neurogenic Cortical Defects in Down Syndrome
title_fullStr DYRK1A-mediated Cyclin D1 Degradation in Neural Stem Cells Contributes to the Neurogenic Cortical Defects in Down Syndrome
title_full_unstemmed DYRK1A-mediated Cyclin D1 Degradation in Neural Stem Cells Contributes to the Neurogenic Cortical Defects in Down Syndrome
title_short DYRK1A-mediated Cyclin D1 Degradation in Neural Stem Cells Contributes to the Neurogenic Cortical Defects in Down Syndrome
title_sort dyrk1a-mediated cyclin d1 degradation in neural stem cells contributes to the neurogenic cortical defects in down syndrome
topic Original Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4484814/
https://www.ncbi.nlm.nih.gov/pubmed/26137553
http://dx.doi.org/10.1016/j.ebiom.2015.01.010
work_keys_str_mv AT najassonia dyrk1amediatedcyclind1degradationinneuralstemcellscontributestotheneurogeniccorticaldefectsindownsyndrome
AT arranzjuan dyrk1amediatedcyclind1degradationinneuralstemcellscontributestotheneurogeniccorticaldefectsindownsyndrome
AT lochheadpamelaa dyrk1amediatedcyclind1degradationinneuralstemcellscontributestotheneurogeniccorticaldefectsindownsyndrome
AT ashfordannel dyrk1amediatedcyclind1degradationinneuralstemcellscontributestotheneurogeniccorticaldefectsindownsyndrome
AT oxleydavid dyrk1amediatedcyclind1degradationinneuralstemcellscontributestotheneurogeniccorticaldefectsindownsyndrome
AT delabarjeanm dyrk1amediatedcyclind1degradationinneuralstemcellscontributestotheneurogeniccorticaldefectsindownsyndrome
AT cooksimonj dyrk1amediatedcyclind1degradationinneuralstemcellscontributestotheneurogeniccorticaldefectsindownsyndrome
AT barallobremariajose dyrk1amediatedcyclind1degradationinneuralstemcellscontributestotheneurogeniccorticaldefectsindownsyndrome
AT arbonesmarial dyrk1amediatedcyclind1degradationinneuralstemcellscontributestotheneurogeniccorticaldefectsindownsyndrome