Dyrk1a-mediated function in brain neurogenesis: interactors and cell cycle parameters in neural progenitors

Trabajo fin de máster.-- Universitat Pompeu Fabra.DYRK1A is a kinase codified on human chromosome 21, within the Down syndrome critical region. It regulates proliferation, neurogenesis, cell death and synaptic plasticity. Loss-of-function mutations in DYRK1A gene leads to DYRK1A haploinsufficiency syndrome, a disorder that exhibit developmental delay, microcephaly, and epileptic seizures. In the embryo, the increase in Dyrk1a gene dosage negatively regulates cell cycle progression in neural progenitors by controlling the levels of Cyclin D and p27kip1. Here, we assess the impact of DYRK1A loss-of-function in two mouse models: a complete heterozygous mutant that models the human syndrome and a neural specific conditional Dyrk1a KO mouse. Our results suggest that Dyrk1a loss-of-function shortens G1-phase and elongates the S-phase in cortical neural progenitors, which could underly the changes in neuron production observed in the cerebral cortex of the two Dyrk1a mutants analyzed. DYRK1A phosphorylates and interacts with a variety of proteins. Here we have validated DOCK7 and LZTS1 as DYRK1A interactors by immunoprecipitation. Dyrk1a haploinsufficiency do not alter the protein levels of those molecules suggesting that DYRK1A do not induce protein degradation or stabilization as it does with other substrates. Altogether our results contribute to understand the developmental role of DYRK1A in the dorsal telencephalon.Peer reviewe