Role of DYRK1A in the development of the cerebral cortex : Implication in Down Syndrome
In this work we have assessed the possible contribution of the human chromosome-21 gene DYRK1A in the developmental cortical alterations associated with Down Syndrome using the mBACTgDyrk1a mouse, which carries 3 copies of Dyrk1a, and a trisomic model of the syndrome, the Ts65Dn mouse. We show that...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2014 |
| País: | España |
| Institución: | CBUC, CESCA |
| Repositorio: | TDR. Tesis Doctorales en Red |
| OAI Identifier: | oai:www.tdx.cat:10803/380895 |
| Acceso en línea: | http://hdl.handle.net/10803/380895 |
| Access Level: | acceso abierto |
| Palabra clave: | Down Syndrome Ts65Dn mouse Brachycephaly Cerebral cortex Glutamatergic neurons GABAergic interneurons Development Dorsal telencephalon Medial ganglionic eminence Neurogenesis DYRK1A mBACTgDyrk1a mouse Radial glial progenitors Intermediate progenitor Assymetirc division Cell cycle Cyclin D1 G1 phase Síndrome de Down Ratolí Ts65Dn Braquicefàlia Escorça cerebral Neurones glutamatèrgiques Neurones GABAèrgiques Telencèfal dorsal Eminència ganglionar medial Neurogènesi Ratolí mBACTgDyrk1a Progenitors Glia radial Progenitors intermitjos Divisió assimètrica Cicle cel·lular Ciclina D1 616.8 |
| Sumario: | In this work we have assessed the possible contribution of the human chromosome-21 gene DYRK1A in the developmental cortical alterations associated with Down Syndrome using the mBACTgDyrk1a mouse, which carries 3 copies of Dyrk1a, and a trisomic model of the syndrome, the Ts65Dn mouse. We show that trisomy of Dyrk1a changes the cell cycle parameters of dorsal telencephalic radial glial (RG) progenitors and the division mode of these progenitors leading to a deficit in glutamatergic neurons that persist until the adulthood. We demonstrate that Dyrk1a is the triplicated gene that causes the deficit in early-born cortical glutamatergic neurons in Ts65Dn mice. Moreover, we provide evidences indicating that DYRK1A-mediated degradation of Cyclin D1 is the underlying mechanism of the cell cycle defects in both, mBACTgDyrk1a and Ts65Dn dorsal RG progenitors. Finally, we show that early neurogenesis is enhanced in the medial ganglionic eminence of mBACTgDyrk1a embryos resulting in an altered proportion of particular cortical GABAergic neuron types. These results indicate that the overexpression of DYRK1A contributes significantly to the formation of the cortical circuitry in Down syndrome. |
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