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Trabajo presentado en el 17th Spanish Society for Developmental Biology Meeting, celebrado en modalidad virtual del 18 al 20 de noviembre de 2020., DYRK1A (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.

Summary Bone morphogenetic proteins (BMPs) are multitasking secreted factors from the Transforming Growth Factor-β (TGF-β) superfamily 1 , members of which play crucial roles during amniote development 2,3 . BMPs and their canonical signalling through the SMAD1/5/8 transcription factors are known to play key roles during the early steps of central nervous system (CNS) development, influencing events such as neural induction, neural tube closure and dorsal-ventral patterning 4-7 . However, their contribution to the later stages of amniote CNS formation is much less clear. Here we reveal that SMAD1/5 fulfill an evolutionarily conserved role during cortical neurogenesis. Gain- and loss-of-function experiments in chick embryos show that SMAD1/5 activity supports the self-amplification of cortical radial glial cells (RGCs) and impedes their premature differentiation and exhaustion. Using conditional Smad1/5 wt/fl ;Nestin:Cre +/0 (SmadNes) mutant mice, we reveal this role to be evolutionarily conserved in mammals. The sustained reduction in SMAD1/5 activity in mouse RGCs increases the generation of early-born cortical excitatory neurons at the expense of late-born neurons. These SmadNes mutant mice also present microcephaly and overall growth retardation. Genome-wide analysis of the transcriptional changes caused by SMAD1/5 inhibition in cortical RGCs indicates that SMAD1/5 positively regulate the activity of YAP, a master regulator of cell growth and organ size 8 . These findings identify an evolutionarily conserved role for canonical BMP signalling in stem cell maintenance and tissue growth during cortical neurogenesis. We anticipate that the regulation of YAP activity by canonical BMP signalling extends beyond the context of cortical neurogenesis and might be a crucial event regulating growth throughout the CNS and in other tissues.

Comunicación presentada en el 3rd Annual Meeting – ReDevNeural, celebrado en San Feliu del Guixols (España) del 7 al 8 de junio de 2018.