Attenuation of Notch signalling by the Down-syndrome-associated kinase DYRK1A

Fernández-Martı́nez, Javier; Vela, Eva M.; Tora-Ponsioen, Mireille; Ocaña, Oscar H.; Nieto, M. Ángela; Galceran, Juan

doi:10.1242/jcs.044354

Cited by 75 publications

(57 citation statements)

References 54 publications

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“…Moreover, the Notch signaling pathway, which is downregulated by DS-associated kinase DIRK1A (70), is also crucial for maintaining an essential population of NPCs for DG adult neurogenesis (71) and determining cell fate and newborn neuron differentiation (72). Further studies are warranted to identify abnormal neurogenetic pathways in DS and/or their potential exploitation for therapies.…”

Section: Discussionmentioning

confidence: 99%

Lithium rescues synaptic plasticity and memory in Down syndrome mice

Contestabile¹,

Greco²,

Ghezzi³

et al. 2012

J. Clin. Invest.

145

151

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Down syndrome (DS) patients exhibit abnormalities of hippocampal-dependent explicit memory, a feature that is replicated in relevant mouse models of the disease. Adult hippocampal neurogenesis, which is impaired in DS and other neuropsychiatric diseases, plays a key role in hippocampal circuit plasticity and has been implicated in learning and memory. However, it remains unknown whether increasing adult neurogenesis improves hippocampal plasticity and behavioral performance in the multifactorial context of DS. We report that, in the Ts65Dn mouse model of DS, chronic administration of lithium, a clinically used mood stabilizer, promoted the proliferation of neuronal precursor cells through the pharmacological activation of the Wnt/ β-catenin pathway and restored adult neurogenesis in the hippocampal dentate gyrus (DG) to physiological levels. The restoration of adult neurogenesis completely rescued the synaptic plasticity of newborn neurons in the DG and led to the full recovery of behavioral performance in fear conditioning, object location, and novel object recognition tests. These findings indicate that reestablishing a functional population of hippocampal newborn neurons in adult DS mice rescues hippocampal plasticity and memory and implicate adult neurogenesis as a promising therapeutic target to alleviate cognitive deficits in DS patients.

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Section: Discussionmentioning

confidence: 99%

Lithium rescues synaptic plasticity and memory in Down syndrome mice

Contestabile¹,

Greco²,

Ghezzi³

et al. 2012

J. Clin. Invest.

145

151

View full text Add to dashboard Cite

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“…The DYRK(1A/1B)/HAN11 complex may also function at the crossroads of cellular proliferation and differentiation. Mammalian DYRK1A has also been shown to interfere with the Notch signaling pathway and the NFAT and Gli transcriptional programs, which are linked to cell fate and differentiation activities (3,19,30,40). DYRK1B has been shown to regulate differentiation and apoptosis (reviewed in reference 22).…”

Section: Discussionmentioning

confidence: 99%

Adenovirus Type 5 E1A and E6 Proteins of Low-Risk Cutaneous Beta-Human Papillomaviruses Suppress Cell Transformation through Interaction with FOXK1/K2 Transcription Factors

Komorek

Kuppuswamy

Subramanian

et al. 2010

J Virol

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The adenovirus (Adv) oncoprotein E1A stimulates cell proliferation and inhibits differentiation. These activities are primarily linked to the N-terminal region (exon 1) of E1A, which interacts with multiple cellular protein complexes. The C terminus (exon 2) of E1A antagonizes these processes, mediated in part through interaction with C-terminal binding proteins 1 and 2 (CtBP1/2). To identify additional cellular E1A targets that are involved in the modulation of E1A C-terminus-mediated activities, we undertook tandem affinity purification of E1A-associated proteins. Through mass spectrometric analysis, we identified several known E1A-interacting proteins as well as novel E1A targets, such as the forkhead transcription factors, FOXK1/K2. We identified a Ser/Thr-containing sequence motif in E1A that mediated interaction with FOXK1/K2. We demonstrated that the E6 proteins of two beta-human papillomaviruses (HPV14 and HPV21) associated with epidermodysplasia verruciformis also interacted with FOXK1/K2 through a motif similar to that of E1A. The E1A mutants deficient in interaction with FOXK1/K2 induced enhanced cell proliferation and oncogenic transformation. The hypertransforming activity of the mutant E1A was suppressed by HPV21 E6. An E1A-E6 chimeric protein containing the Ser/Thr domain of the E6 protein in E1A interacted efficiently with FOXK1/K2 and inhibited cell transformation. Our results suggest that targeting FOXK1/K2 may be a common mechanism for certain beta-HPVs and Adv5. E1A exon 2 mutants deficient in interaction with the dual-specificity kinases DYRK1A/1B and their cofactor HAN11 also induced increased cell proliferation and transformation. Our results suggest that the E1A C-terminal region may suppress cell proliferation and oncogenic transformation through interaction with three different cellular protein complexes: FOXK1/K2, DYRK(1A/1B)/HAN11, and CtBP1/2. Adenovirus (Adv) is a model DNA tumor virus that has been widely used to decipher critical pathways of oncogenesis. The adenovirus early gene E1A is an intensely investigated viral oncogene and has been instrumental in uncovering common cell cycle-regulatory pathways shared by other DNA tumor virus oncogenes such as human papillomavirus (HPV) E7 (reviewed in reference 43) and simian virus 40 (SV40) T antigen (Ag) (reviewed in reference 9). E1A promotes cellular entry into S phase by deregulating the cell cycle and activates other early viral genes to facilitate viral replication. As a consequence of nonproductive infection, E1A immortalizes rodent cells and also oncogenically transforms these cells in cooperation with other viral or cellular oncogenes (27,32,52,62).The E1A gene encodes two major protein isoforms that are expressed from two mRNAs (13S and 12S) generated by alternative RNA splicing. The 13S mRNA encodes a 289-aminoacid ([aa] 289R) protein while the 12S mRNA encodes a 243-amino-acid (243R) protein. The 289R and 243R proteins differ by a 46-amino-acid region that is unique to 289R. The 243R protein is not required for viral replica...

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“…Interaction of MNB/DYRK1A with NOTCH signaling in neural proliferation and neuronal differentiation In order to gain insight into the mechanism by which Mnb/Dyrk1a suppresses NOTCH signaling during neurogenesis, we investigated whether MNB/DYRK1A acts upstream or downstream of NICD, as it has been reported that MNB/DYRK1A phosphorylates the NICD in cell lines (Fernandez-Martinez et al, 2009). To this end, we transfected embryonic chick spinal cord cells with Mnb/Dyrk1a + NICD or NICD alone, and we analyzed the capacity of the transfected cells to proliferate.…”

Section: Expression (mentioning

confidence: 99%

Transient expression of Mnb/Dyrk1a couples cell cycle exit and differentiation of neuronal precursors by inducing p27KIP1 expression and suppressing NOTCH signaling

Hämmerle¹,

Ulin²,

Guimerà³

et al. 2011

Development

121

101

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SUMMARYThe decision of a neural precursor to stop dividing and begin its terminal differentiation at the correct place, and at the right time, is a crucial step in the generation of cell diversity in the nervous system. Here, we show that the Down's syndrome candidate gene (Mnb/Dyrk1a) is transiently expressed in prospective neurons of vertebrate CNS neuroepithelia. The gain of function (GoF) of Mnb/Dyrk1a induced proliferation arrest. Conversely, its loss of function (LoF) caused over proliferation and cell death. We found that MNB/DYRK1A is both necessary and sufficient to upregulate, at transcriptional level, the expression of the cyclin-dependent kinase inhibitor p27 KIP1 in the embryonic chick spinal cord and mouse telencephalon, supporting a regulatory role for MNB/DYRK1A in cell cycle exit of vertebrate CNS neurons. All these actions required the kinase activity of MNB/DYRK1A. We also observed that MNB/DYRK1A is co-expressed with the NOTCH ligand Delta1 in single neuronal precursors. Furthermore, we found that MNB/DYRK1A suppressed NOTCH signaling, counteracted the pro-proliferative action of the NOTCH intracellular domain (NICD), stimulated Delta1 expression and was required for the neuronal differentiation induced by the decrease in NOTCH signaling. Nevertheless, although Mnb/Dyrk1a GoF led to extensive withdrawal of neuronal precursors from the cell cycle, it was insufficient to elicit their differentiation. Remarkably, a transient (ON/OFF) Mnb/Dyrk1a GoF efficiently induced neuronal differentiation. We propose that the transient expression of MNB/DYRK1A in neuronal precursors acts as a binary switch, coupling the end of proliferation and the initiation of neuronal differentiation by upregulating p27KIP1 expression and suppressing NOTCH signaling.

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Attenuation of Notch signalling by the Down-syndrome-associated kinase DYRK1A

Cited by 75 publications

References 54 publications

Lithium rescues synaptic plasticity and memory in Down syndrome mice

Lithium rescues synaptic plasticity and memory in Down syndrome mice

Adenovirus Type 5 E1A and E6 Proteins of Low-Risk Cutaneous Beta-Human Papillomaviruses Suppress Cell Transformation through Interaction with FOXK1/K2 Transcription Factors

Transient expression of Mnb/Dyrk1a couples cell cycle exit and differentiation of neuronal precursors by inducing p27KIP1 expression and suppressing NOTCH signaling

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