Dyrk1A Overexpression Inhibits Proliferation and Induces Premature Neuronal Differentiation of Neural Progenitor Cells

Abstract

Dyrk1A is a member of the mammalian Dyrk [dual-specificity tyrosine-(Y)-phosphorylation regulated kinase] family of protein kinasesthat is expressed at high levels in the brain, but its role in the development and function of this organ is not well understood. The human DYRK1A gene is located on trisomic chromosome 21 in Down syndrome (DS) patients, leading to its overexpression. Dyrk1A is also overexpressed in animal models of DS and in gene-specific transgenic mice that consistently exhibit cognitive impairment. To elucidate the cellular and molecular mechanisms that are affected by increased levels of Dyrk1A in the developing brain, we overexpressed this kinase in the embryonic mouse neocortex using the in utero electroporation technique. We found that Dyrk1A overexpression inhibits neural cell proliferation and promotes premature neuronal differentiation in the developing cerebral cortex without affecting cell fate and layer positioning. These effects are dependent on the Dyrk1A kinase activity and are mediated by the nuclear export and degradation of cyclin D1. This study identifies specific Dyrk1A-induced mechanisms that disrupt the normal process of corticogenesis and possibly contribute to cognitive impairment observed in DS patients and animal models.

Increased dosage of DYRK1A and DSCR1 delays neuronal differentiation in neocortical progenitor cells

“…S8). Our findings are in agreement with the study by Yabut et al (2010) and imply that levels of DYRK1A dosage influence downstream pathways differently.…”

“…Of note, a previous study has demonstrated that, in contrast to our study, DYRK1A electroporation in the mouse neocortex suppressed progenitor proliferation via misregulation of cell cycle regulators and leads to precocious neuronal differentiation that is not seen in DS model mice (Yabut et al 2010). Since expression levels of DYRK1A were not examined in progenitors in Yabut et al (2010), we presumed that a much higher dosage of DYRK1A might be expressed in their study, thereby causing a different phenotype.…”

“…Since expression levels of DYRK1A were not examined in progenitors in Yabut et al (2010), we presumed that a much higher dosage of DYRK1A might be expressed in their study, thereby causing a different phenotype. To test this idea, we electroporated a higher concentration (5 mg/mL) of the DYRK1A-expressing plasmids in progenitors.…”

Dyrk1A Phosphorylates p53 and Inhibits Proliferation of Embryonic Neuronal Cells

“…7I), but not other CDK inhibitors, including p27 KIP1 and p15 INK4B (data not shown). Similar to our finding, Yabut et al also reported very recently that transiently overexpressed Dyrk1A by in utero electroporation inhibits neural cell proliferation in embryonic mouse neocortex (41). Although more studies should be performed, the current finding indicates that Dyrk1A overexpression leads to impaired neuronal proliferation through the signaling pathway containing p53 and p21 CIP1 during late embryonic brain development.…”

“…Dyrk1A is also known to phosphorylate proteins associated with mRNA splicing (Cyclin L2, SF2, and SF3) and translation (eIF2B⑀) (42). Interestingly, Yabut et al recently reported that transiently overexpressed Dyrk1A by in utero electroporation inhibits neural cell proliferation in embryonic mouse neocortex, in which the nuclear export and degradation of cyclin D1 could act as a key cell cycle modulator (41). This study also supports our finding in several aspects.…”