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DYRK1A controls replication-associated damage in the developing brain

AuthorsTrujillano, Alejandro; Pijuan, Isabel; Barallobre, María-José CSIC ORCID ; Arbones, Maria L. CSIC ORCID
Issue Date18-Nov-2020
Citation17th Spanish Society for Developmental Biology Meeting (2020)
AbstractDYRK1A (Dual specificity Tyrosine Phosphorylation Regulated Kinase 1A) is encoded by a dosage-dependent gene and it is involved in neurogenesis and neuron differentiation. The overexpression of DYRK1A causes some of the neurological alterations associated to Down syndrome while its haploinsufficiency leads to developmental delay and microcephaly in both humans and mice. Mouse Dyrk1a-/- embryos die @ at E11 limiting the use of this model to study brain development. In this work we have used a conditional knockout mouse model (Dyrk1aNes) in which Dyrk1a was deleted in neural progenitors before the onset of neurogenesis. Dyrk1aNes embryos presented a reduction of brain parenchyma that was notorious before birth (E19) and very prominent in the striatum and other ventral regions. Staining with antibodies against the active form of caspase3 (CASP3) revealed an increase in apoptotic progenitors and differentiating neurons in Dyrk1aNes embryos. Apoptosis in Dyrk1aNes mutants was already significant in the ventral telencephalon at E11 and progressively increased as neurogenesis advances, affecting dorsal telencephalic regions by E13. Alterations in the levels of the cell cycle regulators Cyclin D1 and D2 and the number of progenitors and neurons that were indicative of defects in neurogenesis were also detected in the dorsal telencephalon of E11-E12 Dyrk1aNes embryos. E11-E13 Dyrk1aNes brains showed a significant increase in cells expressing the replication stress marker gH2AX and active p53 (p53+ nuclei) in the same telencephalic regions labelled for CASP3, suggesting that apoptosis is these brains is p53-dependent and likely triggered by activation of DNA repair pathways. Collectively, these results indicate that DYRK1A is necessary for DNA repair and cell cycle progression of neural brain progenitors.
DescriptionTrabajo presentado en el 17th Spanish Society for Developmental Biology Meeting, celebrado en modalidad virtual del 18 al 20 de noviembre de 2020.
Appears in Collections:(IBMB) Comunicaciones congresos
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