Dyrk1A overexpression inhibits proliferation and induces premature neuronal differentiation of neural progenitor cells.
Dyrk1A is a member of the mammalian Dyrk [dual-specificity tyrosine-(Y)-phosphorylation regulated kinase] family of protein kinases that 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.
Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, USA.
Odessa
O
Yabut
Jason
J
Domogauer
Gabriella
G
D'Arcangelo
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002540:Cerebral Cortex / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006131:Growth Inhibitors / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D000097603:Dyrk Kinases
D006131:Growth Inhibitors; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D000097603:Dyrk Kinases