title: DYRK1A-mediated Cyclin D1 Degradation in Neural Stem Cells Contributes to the Neurogenic Cortical Defects in Down Syndrome.
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.
authors.affiliation: Department of Developmental Biology, Instituto de Biología Molecular de Barcelona, CSIC, and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 08028 Barcelona, Spain.
authors.forename: Sònia
authors.initials: S
authors.lastname: Najas
authors.affiliation: Department of Developmental Biology, Instituto de Biología Molecular de Barcelona, CSIC, and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 08028 Barcelona, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Arranz
authors.affiliation: Signalling Programme, The Babraham Institute, Babraham Research Campus, CB22 3AT Cambridge, UK.
authors.forename: Pamela A
authors.initials: PA
authors.lastname: Lochhead
authors.affiliation: Signalling Programme, The Babraham Institute, Babraham Research Campus, CB22 3AT Cambridge, UK.
authors.forename: Anne L
authors.initials: AL
authors.lastname: Ashford
authors.affiliation: Proteomics Group, The Babraham Institute, Babraham Research Campus, CB22 3AT Cambridge, UK.
authors.forename: David
authors.initials: D
authors.lastname: Oxley
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, Inserm, CNRS, UM 75, U 1127, UMR 7225, ICM, 75013 Paris, France.
authors.forename: Jean M
authors.initials: JM
authors.lastname: Delabar
authors.affiliation: Signalling Programme, The Babraham Institute, Babraham Research Campus, CB22 3AT Cambridge, UK.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Cook
authors.affiliation: Department of Developmental Biology, Instituto de Biología Molecular de Barcelona, CSIC, and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 08028 Barcelona, Spain.
authors.forename: María José
authors.initials: MJ
authors.lastname: Barallobre
authors.affiliation: Department of Developmental Biology, Instituto de Biología Molecular de Barcelona, CSIC, and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 08028 Barcelona, Spain.
authors.forename: Maria L
authors.initials: ML
authors.lastname: Arbonés
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000473:pathology; D019938:Cyclin D1 / Q000378:metabolism*; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000235:genetics*; D016193:G1 Phase / Q000235:genetics; D018628:Gene Dosage / Q000235:genetics; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058953:Neural Stem Cells / Q000378:metabolism*; D055495:Neurogenesis / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism*; D013687:Telencephalon / Q000166:cytology; D014314:Trisomy / Q000235:genetics; D000097603:Dyrk Kinases
chemical_list: D019938:Cyclin D1; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D000097603:Dyrk Kinases; C530104:CCND1 protein, human
keywords: Cell cycle regulation; Cerebral cortex development; DS, Down syndrome; DYRK kinases; IP, intermediate progenitor; Intellectual disability; NSC, neural stem cell; Neurodevelopmental disorders; RG, radial glia; SVZ, subventricular zone; Trisomy 21; VZ, ventricular zone