DYRK1A: A master regulatory protein controlling brain growth

Guedj, Fayçal; Pereira, Patricia Lopes; Najas, Sònia; Barallobre, Marı́a José; Chabert, Caroline; Souchet, Benoît; Sebrié, Catherine; Verney, Catherine; Hérault, Yann; Arbonés, Mariona; Delabar, Jean Maurice

doi:10.1016/j.nbd.2012.01.007

Cited by 132 publications

(137 citation statements)

References 62 publications

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“…However, when the total number of cells was quantified in these structures, both TS and CO mice with reduced Dyrk1A copy numbers presented a reduction in the number of cells (GL: 'Dyrk1A': F(1,21)=11.73, p=0.002; ''karyotype' x 'Dyrk1A'': F(1,21)=0.44, p=0.51, figure 1C; SGZ: 'Dyrk1A': F(1,21)=8.89, p=0.007; ''karyotype' x 'Dyrk1A'': F(1,21)=1.46, p=0.024, figure 1E). The fact that the number of cells was lower in the CO +/-group than in the CO +/+ group reflects the well-documented reduction in hippocampal size observed in this group of animals (Guedj et al, 2012). However, when this measure was corrected after considering the area or volume of these areas, the animals showed normal cell densities, indicating that reducing a functional copy of this gene did not affect senescence in the CO +/-hippocampus.…”

Section: Accepted Manuscriptmentioning

confidence: 76%

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Normalizing the gene dosage of Dyrk1A in a mouse model of Down syndrome rescues several Alzheimer's disease phenotypes

García-Cerro

Rueda

Vidal

et al. 2017

Neurobiology of Disease

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The intellectual disability that characterizes Down syndrome (DS) is primarily caused by prenatal changes in central nervous system growth and differentiation. However, in later life stages, the cognitive abilities of DS individuals progressively decline due to accelerated aging and the development of Alzheimer's disease (AD) neuropathology. The AD neuropathology in DS has been related to the overexpression of several genes encoded by Hsa21 including DYRK1A (dualspecificity tyrosine-(Y)-phosphorylation regulated kinase 1A), which encodes a protein kinase that performs crucial functions in the regulation of multiple signaling pathways that contribute to normal brain development and adult brain physiology. Studies performed in vitro and in vivo in animal models overexpressing this gene have demonstrated that the DYRK1A gene also plays a crucial role in several neurodegenerative processes found in DS. The Ts65Dn (TS) mouse bears a partial triplication of several Hsa21 orthologous genes, including Dyrk1A, and replicates many DS-like abnormalities, including age-dependent cognitive decline, cholinergic neuron degeneration, increased levels of APP and Aβ, and tau hyperphosphorylation. To use a more direct approach to evaluate the role of the gene dosage of Dyrk1A on the neurodegenerative profile of this model, TS mice were crossed with Dyrk1A KO mice to obtain mice with a triplication of a segment of Mmu16 that includes this gene, mice that are trisomic for the same genes but only carry two copies of Dyrk1A, euploid mice with a normal Dyrk1A dosage, and CO animals with a single copy of Dyrk1A. Normalizing the gene dosage of Dyrk1A in the TS mouse rescued the density of senescent cells in the cingulate cortex, hippocampus and septum, prevented cholinergic neuron degeneration, and reduced App expression in the hippocampus, Aβ load in the cortex and hippocampus, the expression of phosphorylated tau at the Ser202 residue in the hippocampus and cerebellum and the levels of total tau in the cortex, hippocampus and cerebellum. Thus, the present study provides further support for the role of the Dyrk1A gene in several AD-like phenotypes found in TS mice and indicates that this gene could be a therapeutic target to treat AD in DS.

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Section: Accepted Manuscriptmentioning

confidence: 76%

“…This gene encodes a protein kinase that performs crucial functions in the regulation of cell proliferation and multiple signaling pathways (Guedj et al, 2012;Becker and Sippl, 2011) that contribute to normal brain development and adult brain physiology (Becker and Sippl, 2011;Tejedor and Hämmerle, 2011).…”

Section: Introductionmentioning

confidence: 99%

Normalizing the gene dosage of Dyrk1A in a mouse model of Down syndrome rescues several Alzheimer's disease phenotypes

García-Cerro

Rueda

Vidal

et al. 2017

Neurobiology of Disease

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“…For example, DYRK1A can activate PI3K/Akt signaling, a pathway largely involved in neuronal development, growth, and survival. 46 DYRK1A also stimulates the activity of ASK1/JNK1, possibly inducing neuronal death and apoptosis. 47 In addition, DYRK1A phosphorylates p53 during embryonic brain development, altering neuronal proliferation.…”

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confidence: 99%

Recent Advances in the Design, Synthesis, and Biological Evaluation of Selective DYRK1A Inhibitors: A New Avenue for a Disease Modifying Treatment of Alzheimer’s?

Smith

Medda

Gokhale

et al. 2012

ACS Chem. Neurosci.

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“…DYRK1A has been implicated as a regulator for CNS development, as Dyrk1a-deficent mice show reduced brain size (Fotaki et al 2002). Also, Dyrk1a transgenic mice display alteration of brain size and neuronal density in the cerebral cortex (Guedj et al 2012). Dscr1 also lies within the centromeric border of the DSCR, encodes for an inhibitor of protein phosphatase calcineurin 1, and often is referred to as Rcan1 (regulator of calcineurin 1) (Rothermel et al 2000).…”

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confidence: 99%

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

Kurabayashi

Sanada

2013

Genes Dev.

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Down's syndrome (DS), a major genetic cause of mental retardation, arises from triplication of genes on human chromosome 21. Here we show that DYRK1A (dual-specificity tyrosine-phosphorylated and -regulated kinase 1A) and DSCR1 (DS critical region 1), two genes lying within human chromosome 21 and encoding for a serine/ threonine kinase and calcineurin regulator, respectively, are expressed in neural progenitors in the mouse developing neocortex. Increasing the dosage of both proteins in neural progenitors leads to a delay in neuronal differentiation, resulting ultimately in alteration of their laminar fate. This defect is mediated by the cooperative actions of DYRK1A and DSCR1 in suppressing the activity of the transcription factor NFATc. In Ts1Cje mice, a DS mouse model, dysregulation of NFATc in conjunction with increased levels of DYRK1A and DSCR1 was observed. Furthermore, counteracting the dysregulated pathway ameliorates the delayed neuronal differentiation observed in Ts1Cje mice. In sum, our findings suggest that dosage of DYRK1A and DSCR1 is critical for proper neurogenesis through NFATc and provide a potential mechanism to explain the neurodevelopmental defects in DS.

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DYRK1A: A master regulatory protein controlling brain growth

Cited by 132 publications

References 62 publications

Normalizing the gene dosage of Dyrk1A in a mouse model of Down syndrome rescues several Alzheimer's disease phenotypes

Normalizing the gene dosage of Dyrk1A in a mouse model of Down syndrome rescues several Alzheimer's disease phenotypes

Recent Advances in the Design, Synthesis, and Biological Evaluation of Selective DYRK1A Inhibitors: A New Avenue for a Disease Modifying Treatment of Alzheimer’s?

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

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