The Down syndrome-related protein kinase DYRK1A phosphorylates p27^Kip1and Cyclin D1 and induces cell cycle exit and neuronal differentiation

Abstract

A fundamental question in neurobiology is how the balance between proliferation and differentiation of neuronal precursors is maintained to ensure that the proper number of brain neurons is generated. Substantial evidence implicates DYRK1A (dual specificity tyrosine-phosphorylation-regulated kinase 1A) as a candidate gene responsible for altered neuronal development and brain abnormalities in Down syndrome. Recent findings support the hypothesis that DYRK1A is involved in cell cycle control. Nonetheless, how DYRK1A contributes to neuronal cell cycle regulation and thereby affects neurogenesis remains poorly understood. In the present study we have investigated the mechanisms by which DYRK1A affects cell cycle regulation and neuronal differentiation in a human cell model, mouse neurons, and mouse brain. Dependent on its kinase activity and correlated with the dosage of overexpression, DYRK1A blocked proliferation of SH-SY5Y neuroblastoma cells within 24 h and arrested the cells in G1 phase. Sustained overexpression of DYRK1A induced G0 cell cycle exit and neuronal differentiation. Furthermore, we provide evidence that DYRK1A modulated protein stability of cell cycle-regulatory proteins. DYRK1A reduced cellular Cyclin D1 levels by phosphorylation on Thr286, which is known to induce proteasomal degradation. In addition, DYRK1A phosphorylated p27Kip1 on Ser10, resulting in protein stabilization. Inhibition of DYRK1A kinase activity reduced p27Kip1 Ser10 phosphorylation in cultured hippocampal neurons and in embryonic mouse brain. In aggregate, these results suggest a novel mechanism by which overexpression of DYRK1A may promote premature neuronal differentiation and contribute to altered brain development in Down syndrome.

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“…Cyclin D1 expression is upregulated by mitogenic signaling through the Ras-signaling pathway involving Ras/Raf/mitogen-activated protein [21]. Cyclin D1 levels are also posttranslationally regulated by its degradation through the following ubiquitin-proteasome pathway.…”

DYRK1A regulates Hap1–Dcaf7/WDR68 binding with implication for delayed growth in Down syndrome

“…Our data have shown that loss of Hap1 can lead to enhanced interaction between Dcaf7 and DYRK1A, resulting in an increase in DYRK1A. It has been reported that increased DYRK1A can affect cell-cycle regulation and neuronal differentiation by reducing cyclin D1 and the cyclindependent kinase inhibitor p21 (49,50), two important proteins that promote neuronal differentiation (50)(51)(52)(53)(54). Thus, we isolated hypothalamic tissues from WT and Hap1-KO postnatal pups and performed Western blotting with anti-cyclin D1 and anti-p21.…”

Ten new cases further delineate the syndromic intellectual disability phenotype caused by mutations in DYRK1A

“…18,19,21,44,45 The reduced brain size may be partially explained by the dual role of DYRK1A in inhibiting the proliferation of neuronal progenitors via suppression of NOTCH signaling and Cyclin D1 while also promoting neurogenesis by stabilizing the cyclindependent kinase inhibitor p27 (KIP1) . 46,47 In addition, DYRK1A interacts with the microtubule and actin cytoskeletal networks to regulate neurite outgrowth and synaptogenesis. [48][49][50] Through these mechanisms, haploinsuffciency of DYRK1A presumably leads to augmented neuronal precursor proliferation and apoptosis, decreased neurogenesis and abnormal neuritogenesis.…”