cyclin-d1 and Down-Syndrome

Topics: Cyclin D1; Down Syndrome; Dyrk Kinases; G1 Phase; Humans; Neurogenesis; Protein Serine-Threonine Kinases; Protein-Tyrosine Kinases

Topics: Antigens, CD; Cadherins; Cell Cycle Checkpoints; Cell Proliferation; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p21; Down Syndrome; Epithelial-Mesenchymal Transition; Gene Expression Regulation; HaCaT Cells; Humans; Keratinocytes; Light; Microbial Viability; Pseudomonas aeruginosa; Snail Family Transcription Factors; Staphylococcus aureus

Down syndrome (DS) caused by trisomy of chromosome 21 is the most common genetic cause of intellectual disability. Although the prenatal diagnosis of DS has become feasible, there are no therapies available for the rescue of DS-related neurocognitive impairment. A growth inducer newly identified in our screen of neural stem cells (NSCs) has potent inhibitory activity against dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) and was found to rescue proliferative deficits in Ts65Dn-derived neurospheres and human NSCs derived from individuals with DS. The oral administration of this compound, named ALGERNON (altered generation of neurons), restored NSC proliferation in murine models of DS and increased the number of newborn neurons. Moreover, administration of ALGERNON to pregnant dams rescued aberrant cortical formation in DS mouse embryos and prevented the development of abnormal behaviors in DS offspring. These data suggest that the neurogenic phenotype of DS can be prevented by ALGERNON prenatal therapy.

Topics: Animals; Cerebral Cortex; Cognition; Cyclin D1; Dentate Gyrus; Down Syndrome; Dyrk Kinases; Female; Fetal Therapies; HEK293 Cells; Humans; Learning; Male; Mice; Neural Stem Cells; Neurogenesis; Pregnancy; Protein Serine-Threonine Kinases; Protein-Tyrosine Kinases

Alterations in cerebral cortex connectivity lead to intellectual disability and in Down syndrome, this is associated with a deficit in cortical neurons that arises during prenatal development. However, the pathogenic mechanisms that cause this deficit have not yet been defined. Here we show that the human DYRK1A kinase on chromosome 21 tightly regulates the nuclear levels of Cyclin D1 in embryonic cortical stem (radial glia) cells, and that a modest increase in DYRK1A protein in transgenic embryos lengthens the G1 phase in these progenitors. These alterations promote asymmetric proliferative divisions at the expense of neurogenic divisions, producing a deficit in cortical projection neurons that persists in postnatal stages. Moreover, radial glial progenitors in the Ts65Dn mouse model of Down syndrome have less Cyclin D1, and Dyrk1a is the triplicated gene that causes both early cortical neurogenic defects and decreased nuclear Cyclin D1 levels in this model. These data provide insights into the mechanisms that couple cell cycle regulation and neuron production in cortical neural stem cells, emphasizing that the deleterious effect of DYRK1A triplication in the formation of the cerebral cortex begins at the onset of neurogenesis, which is relevant to the search for early therapeutic interventions in Down syndrome.

Topics: Animals; Cerebral Cortex; Cyclin D1; Disease Models, Animal; Down Syndrome; Dyrk Kinases; G1 Phase; Gene Dosage; Humans; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neural Stem Cells; Neurogenesis; Protein Serine-Threonine Kinases; Protein-Tyrosine Kinases; Telencephalon; Trisomy

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 p27(Kip1) on Ser10, resulting in protein stabilization. Inhibition of DYRK1A kinase activity reduced p27(Kip1) 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.

Topics: Animals; Brain; Cell Cycle; Cell Differentiation; Cell Line; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p27; Down Syndrome; Dyrk Kinases; Humans; Mice, Inbred ICR; Neurogenesis; Neurons; Phosphorylation; Primary Cell Culture; Protein Serine-Threonine Kinases; Protein-Tyrosine Kinases; Serine; Threonine

Mammalian cells have a remarkable capacity to compensate for heterozygous gene loss or extra gene copies. One exception is Down syndrome (DS), where a third copy of chromosome 21 mediates neurogenesis defects and lowers the frequency of solid tumors. Here we combine live-cell imaging and single-cell analysis to show that increased dosage of chromosome 21-localized Dyrk1a steeply increases G1 cell cycle duration through direct phosphorylation and degradation of cyclin D1 (CycD1). DS-derived fibroblasts showed analogous cell cycle changes that were reversed by Dyrk1a inhibition. Furthermore, reducing Dyrk1a activity increased CycD1 expression to force a bifurcation, with one subpopulation of cells accelerating proliferation and the other arresting proliferation by costabilizing CycD1 and the CDK inhibitor p21. Thus, dosage of Dyrk1a repositions cells within a p21-CycD1 signaling map, directing each cell to either proliferate or to follow two distinct cell cycle exit pathways characterized by high or low CycD1 and p21 levels.

Topics: Cell Line, Tumor; Cell Proliferation; Cell Tracking; Chromosomes, Human, Pair 21; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p21; Down Syndrome; Dyrk Kinases; Fibroblasts; G1 Phase; Gene Expression Regulation; Gene Knockdown Techniques; Humans; Microscopy, Fluorescence; Microscopy, Video; Phosphorylation; Protein Serine-Threonine Kinases; Protein Stability; Protein-Tyrosine Kinases; ras Proteins; RNA Interference; Signal Transduction; Time Factors; Time-Lapse Imaging; Transfection