Modelling and rescuing neurodevelopmental defect of Down syndrome using induced pluripotent stem cells from monozygotic twins discordant for trisomy 21

Hibaoui, Youssef; Grad, Iwona; Letourneau, Audrey; Sailani, M Reza; Dahoun, Sophie; Santoni, Federico A; Gimelli, Stefania; Guipponi, Michel; Pelte, Marie Françoise; Béna, Frédérique; Antonarakis, Stylianos E; Feki, Anis

doi:10.1002/emmm.201302848

Cited by 170Down syndrome and intellectual disability researchPluripotent Stem Cells ResearchNeurogenesis and neuroplasticity mechanisms

Modelling and rescuing neurodevelopmental defect of Down syndrome using induced pluripotent stem cells from monozygotic twins discordant for trisomy 21

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Hibaoui, Youssef, Grad, Iwona, Letourneau, Audrey, Sailani, M Reza, Dahoun, Sophie, Santoni, Federico A, Gimelli, Stefania, Guipponi, Michel +4 more·2014·EMBO Molecular Medicine

DOI 10.1002/emmm.201302848PMC PMC3927959

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Abstract

Down syndrome (trisomy 21) is the most common viable chromosomal disorder with intellectual impairment and several other developmental abnormalities. Here, we report the generation and characterization of induced pluripotent stem cells (iPSCs) derived from monozygotic twins discordant for trisomy 21 in order to eliminate the effects of the variability of genomic background. The alterations observed by genetic analysis at the iPSC level and at first approximation in early development illustrate the developmental disease transcriptional signature of Down syndrome. Moreover, we observed an abnormal neural differentiation of Down syndrome iPSCs in vivo when formed teratoma in NOD‐SCID mice, and in vitro when differentiated into neuroprogenitors and neurons. These defects were associated with changes in the architecture and density of neurons, astroglial and oligodendroglial cells together with misexpression of genes involved in neurogenesis, lineage specification and differentiation. Furthermore, we provide novel evidence that dual‐specificity tyrosine‐( Y )‐phosphorylation regulated kinase 1 A ( DYRK1A ) on chromosome 21 likely contributes to these defects. Importantly, we found that targeting DYRK1A pharmacologically or by shRNA results in a considerable correction of these defects.

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Results from induced pluripotent stem cell studies of neurogenesis are discordant: the generation of neurons from induced pluripotent stem cells has been reported in some studies to be impaired and in others not to be impaired, which may be explained by technical differences in the cell lines and protocols used.
“However, results from these studies are discordant: the generation of neurons from iPSCs has been reported in some studies to be impaired74,77–79 and in others not to be impaired75,80,81, which may be explained by technical differences in the cell lines and protocols used (see Box 1).”
From Consequences of trisomy 21 for brain development in Down syndrome (2024) · cites this paper as [79]
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Analyses of neural progenitor cells arising from trisomy 21 induced pluripotent stem cells have provided conflicting data, with some suggesting that apoptosis is increased and others seeing no effect.
“Analyses of NPCs arising from T21 iPSCs have provided conflicting data, with some suggesting that apoptosis is increased74,79,95 and others seeing no effect75,77,81,96.”
From Consequences of trisomy 21 for brain development in Down syndrome (2024) · cites this paper as [79]
When cultured long enough to enable the generation of astrocytes, trisomy 21 induced pluripotent stem cells generate more astrocytes than control induced pluripotent stem cells, concomitant with a reduction in the generation of neurons.
“Similarly, when cultured for long enough to enable the generation of astrocytes, T21 iPSCs generate more of this cell type than control iPSCs, concomitant with a reduction in the generation of neurons79,82,96,103.”
From Consequences of trisomy 21 for brain development in Down syndrome (2024) · cites this paper as [79]
Trisomic iPSCs show significant increase in astrocyte differentiation.
“A significant increase in astrocytes differentiated from trisomic iPSCs has been reported many times (Briggs et al., 2013; Chen et al., 2014; Hibaoui et al., 2014; Real et al., 2018; Mollo et al., 2021).”
From Neurodevelopment in Down syndrome: Concordance in humans and models (2022) · cites this paper as Hibaoui et al., 2014
Two other studies found decreased number of neurons from trisomic iPSCs.
“However, two other studies, one using a separate isogenic line and one using non-isogenic matched iPSCs found that the trisomic line produced a decreased number of neurons compared to the euploid control (Lu et al., 2013; Hibaoui et al., 2014).”
From Neurodevelopment in Down syndrome: Concordance in humans and models (2022) · cites this paper as Hibaoui et al., 2014

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Mazur‐Kolecka, B., Golabek, A. A., Kida, E., Rabe, A., Hwang, Y., Adayev, T., Węgiel, J., Flory, M. J., Kaczmarski, W., Marchi, E. J., et al. (2012) · Journal of Neuroscience Research · doi:10.1002/jnr.23007 · Cited by 38 · see citing works
Human Pluripotent Stem Cells: Applications and Challenges in Neurological Diseases
Hibaoui, Y., & Féki, A. (2012) · Frontiers in Physiology · doi:10.3389/fphys.2012.00267 · Cited by 35 · see citing works
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NANOG priming before full reprogramming may generate germ cell tumours
Service de gynécologie obstétrique, H. F. H. C., Grad, I., Hibaoui, Y., Jaconi, M. E., Chicha, L., Bergström-Tengzelius, R., Sailani, M. R., Pelte, M., Dahoun, S. P., Mitsiadis, T. A., et al. (2011) · European Cells and Materials · doi:10.22203/ecm.v022a20 · Cited by 28 · see citing works
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Phenazopyridine induces and synchronizes neuronal differentiation of embryonic stem cells
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An additional human chromosome 21 causes suppression of neural fate of pluripotent mouse embryonic stem cells in a teratoma model
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Pluripotent stem cells in disease modelling and drug discovery
Avior, Y., Sagi, I., & Benvenisty, N. (2016) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2015.27 · Cited by 592 · see citing works
A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome
Wiseman, F. K., Al-Janabi, T., Hardy, J., Karmiloff-Smith, A., Nizetic, D., Tybulewicz, V. L. J., Fisher, E. M. C., & Strydom, A. (2015) · Nature Reviews Neuroscience · doi:10.1038/nrn3983 · Cited by 562 · see citing works
Domains of genome-wide gene expression dysregulation in Down’s syndrome
Letourneau, A., Santoni, F. A., Bonilla, X., Sailani, M. R., Gonzalez, D., Kind, J., Chevalier, C., Thurman, R., Sandstrom, R. S., Hibaoui, Y., et al. (2014) · Nature · doi:10.1038/nature13200 · Cited by 319 · see citing works
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Down syndrome and the complexity of genome dosage imbalance
Antonarakis, S. (2016) · Nature reviews genetics · doi:10.1038/nrg.2016.154 · Cited by 264 · see citing works
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Role of astrocyte–synapse interactions in CNS disorders
Blanco‐Suárez, E., Caldwell, A. L. M., & Allen, N. J. (2016) · The Journal of Physiology · doi:10.1113/jp270988 · Cited by 222 · see citing works
3D brain Organoids derived from pluripotent stem cells: promising experimental models for brain development and neurodegenerative disorders
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Human Models Are Needed for Studying Human Neurodevelopmental Disorders
Zhao, X., & Bhattacharyya, A. (2018) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2018.10.009 · Cited by 192 · see citing works
The Down syndrome-related protein kinase DYRK1A phosphorylates p27Kip1and Cyclin D1 and induces cell cycle exit and neuronal differentiation
Soppa, U., Schumacher, J., Florencio Ortiz, V., Pasqualon, T., Tejedor, F., & Becker, W. (2014) · Cell Cycle · doi:10.4161/cc.29104 · Cited by 189 · see citing works
DYRK1A, a dosage-sensitive gene involved in neurodevelopmental disorders, is a target for drug development in down syndrome
Duchon, A., & Herault, Y. (2016) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2016.00104 · Cited by 181 · see citing works
Dysfunction of autophagy and endosomal-lysosomal pathways: Roles in pathogenesis of Down syndrome and Alzheimer’s Disease
Colacurcio, D. J., Pensalfini, A., Jiang, Y., & Nixon, R. A. (2018) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2017.10.001 · Cited by 167 · see citing works
Effects of aneuploidy on cell behaviour and function
Li, R., & Zhu, J. (2022) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-021-00436-9 · Cited by 141 · see citing works
DSCAM/PAK1 pathway suppression reverses neurogenesis deficits in iPSC-derived cerebral organoids from patients with Down syndrome
Tang, X.-Y., Xu, L., Wang, J., Hong, Y., Wang, Y., Zhu, Q., Wang, D., Zhang, X.-Y., Liu, C.-Y., Fang, K.-H., et al. (2021) · Journal of Clinical Investigation · doi:10.1172/jci135763 · Cited by 143 · see citing works
Stem cell models of Alzheimer’s disease: progress and challenges
Arber, C., Lovejoy, C., & Wray, S. (2017) · Alzheimer's Research & Therapy · doi:10.1186/s13195-017-0268-4 · Cited by 143 · see citing works
The GABAergic Hypothesis for Cognitive Disabilities in Down Syndrome
Contestabile, A., Magara, S., & Cancedda, L. (2017) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2017.00054 · Cited by 141 · see citing works
The polyphenols resveratrol and epigallocatechin-3-gallate restore the severe impairment of mitochondria in hippocampal progenitor cells from a Down syndrome mouse model
Valenti, D., Lidia de, B. A. R. I., Rasmo, D. D., Signorile, A., Henrion‐Caude, A., Contestabile, A., & Vacca, R. A. (2016) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2016.03.003 · Cited by 128 · see citing works
An ID2-dependent mechanism for VHL inactivation in cancer
Lee, S. B., Frattini, V., Bansal, M., Castano, A. M., Sherman, D., Hutchinson, K., Bruce, J. N., Califano, A., Liu, G., Cardozo, T. J., et al. (2016) · Nature · doi:10.1038/nature16475 · Cited by 127 · see citing works
Modeling Alzheimer's disease with human induced pluripotent stem (iPS) cells
Mungenast, A. E., Siegert, S., & Tsai, L. (2015) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2015.11.010 · Cited by 127 · see citing works
Neurogenesis impairment: An early developmental defect in Down syndrome
Stagni, F., Giacomini, A., Emili, M., Guidi, S., & Bartesaghi, R. (2018) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2017.07.026 · Cited by 120 · see citing works
Overexpression of Dyrk1A is implicated in several cognitive, electrophysiological and Neuromorphological alterations found in a mouse model of down syndrome
García-Cerro, S., Martínez, P., Vidal, V., Corrales, A., Flórez, J., Vidal, R., Rueda, N., Arbonés, M. L., & Martínez-Cué, C. (2014) · PLoS ONE · doi:10.1371/journal.pone.0106572 · Cited by 104 · see citing works
DYRK1A-mediated cyclin D1 degradation in neural stem cells contributes to the neurogenic cortical defects in down syndrome
Najas, S., Arranz, J., Lochhead, P. A., Ashford, A. L., Oxley, D., Delabar, J. M., Cook, S. J., Barallobre, M. J., & Arbonés, M. L. (2015) · EBioMedicine · doi:10.1016/j.ebiom.2015.01.010 · Cited by 92 · see citing works
Down syndrome: Neurobiological alterations and therapeutic targets
Vacca, R. A., Bawari, S., Valenti, D., Tewari, D., Nabavi, S. F., Shirooie, S., Sah, A. N., Volpicella, M., Braidy, N., & Nabavi, S. M. (2019) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2019.01.001 · Cited by 90 · see citing works
Trans effects of chromosome aneuploidies on DNA methylation patterns in human Down syndrome and mouse models
Mendióroz, M., Do, C., Jiang, X., Liu, C., Darbary, H. K., Lang, C. F., Lin, J. P., Thomas, A. C., Abu-Amero, S. N., Stanier, P., et al. (2015) · Genome biology · doi:10.1186/s13059-015-0827-6 · Cited by 85 · see citing works
Brief Report: Isogenic Induced Pluripotent Stem Cell Lines From an Adult With Mosaic Down Syndrome Model Accelerated Neuronal Ageing and Neurodegeneration
Murray, A., Letourneau, A., Canzonetta, C., Stathaki, E., Gimelli, S., Sloan-Bena, F., Abrehart, R., Goh, P., Lim, S., Baldo, C., et al. (2015) · Stem Cells · doi:10.1002/stem.1968 · Cited by 78 · see citing works
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Comparative performance analysis of human iPSC-derived and primary neural progenitor cells (NPC) grown as neurospheres in vitro
Hofrichter, M., Nimtz, L., Tigges, J., Kabiri, Y., Schröter, F., Royer‐Pokora, B., Hildebrandt, B., Schmuck, M. R., Epanchintsev, A., Theiss, S., et al. (2017) · Stem Cell Research · doi:10.1016/j.scr.2017.10.013 · Cited by 74 · see citing works
DYRK1A Protein, A Promising Therapeutic Target to Improve Cognitive Deficits in Down Syndrome
Féki, A., & Hibaoui, Y. (2018) · Brain Sciences · doi:10.3390/brainsci8100187 · Cited by 71 · see citing works
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mitoXplorer, a visual data mining platform to systematically analyze and visualize mitochondrial expression dynamics and mutations
Yim, A., Koti, P. S., Bonnard, A., Marchianò, F., Dürrbaum, M., Garcı́a-Pérez, C., Villaveces, J. M., Gamal, S., Cardone, G., Perocchi, F., et al. (2019) · Nucleic Acids Research · doi:10.1093/nar/gkz1128 · Cited by 75 · see citing works
Prenatal neurogenesis induction therapy normalizes brain structure and function in Down syndrome mice
Nakano-Kobayashi, A., Awaya, T., Kii, I., Sumida, Y., Okuno, Y., Yoshida, S., Sumida, T., Inoue, H., Hosoya, T., & Hagiwara, M. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1704143114 · Cited by 71 · see citing works
The secretome of induced pluripotent stem cells reduces lung fibrosis in part by hepatocyte growth factor
Gazdhar, A., Grad, I., Tamò, L., Gugger, M., Féki, A., & Geiser, T. (2014) · Stem Cell Research & Therapy · doi:10.1186/scrt513 · Cited by 68 · see citing works
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Use of stem cells as alternative methods to animal experimentation in predictive toxicology
Kim, T., Che, J., & Yun, J.-W. (2019) · Regulatory Toxicology and Pharmacology · doi:10.1016/j.yrtph.2019.03.016 · Cited by 62 · see citing works
An Integrated Human/Murine Transcriptome and Pathway Approach To Identify Prenatal Treatments For Down Syndrome
Guedj, F., Pennings, J. L. A., Massingham, L. J., Wick, H. C., Siegel, A. E., Tantravahi, U., & Bianchi, D. W. (2016) · Scientific Reports · doi:10.1038/srep32353 · Cited by 59 · see citing works
Transcriptome and Proteome Profiling of Neural Induced Pluripotent Stem Cells from Individuals with Down Syndrome Disclose Dynamic Dysregulations of Key Pathways and Cellular Functions
Sobol, M., Klar, J., Laan, L., Shahsavani, M., Schuster, J., Annerén, G., Konzer, A., Mi, J., Bergquist, J., Nordlund, J., et al. (2019) · Molecular Neurobiology · doi:10.1007/s12035-019-1585-3 · Cited by 58 · see citing works
Modeling neurodegenerative diseases with patient-derived induced pluripotent cells: Possibilities and challenges
Poon, A., Zhang, Y., Chandrasekaran, A., Phanthong, P., Schmid, B., Nielsen, T. T., & Freude, K. (2017) · New Biotechnology · doi:10.1016/j.nbt.2017.05.009 · Cited by 53 · see citing works
Multiple functions of DYRK2 in cancer and tissue development
Yoshida, S., & Yoshida, K. (2019) · FEBS Letters · doi:10.1002/1873-3468.13601 · Cited by 52 · see citing works
The Role of Astrocytes in the Development of the Cerebellum
Araújo, A. P. B., Carpi-Santos, R., & Gomes, F. C. A. (2019) · The Cerebellum · doi:10.1007/s12311-019-01046-0 · Cited by 53 · see citing works
Network analysis of Down syndrome and SARS-CoV-2 identifies risk and protective factors for COVID-19
Toma, I. D., & Dierssen, M. (2021) · Scientific Reports · doi:10.1038/s41598-021-81451-w · Cited by 51 · see citing works
GSK3ß‐dependent dysregulation of neurodevelopment in SPG11‐patient induced pluripotent stem cell model
Mishra, H. K., Prots, I., Havlicek, S., Kohl, Z., Pérez‐Brangulí, F., Boerstler, T., Anneser, L., Minakaki, G., Wend, H., Hampl, M., et al. (2016) · Annals of Neurology · doi:10.1002/ana.24633 · Cited by 51 · see citing works
DNA-Methylation Patterns in Trisomy 21 Using Cells from Monozygotic Twins
Sailani, M. R., Santoni, F. A., Letourneau, A., Borel, C., Makrythanasis, P., Hibaoui, Y., Popadin, K. Y., Bonilla, X., Guipponi, M., Gehrig, C., et al. (2015) · PLoS ONE · doi:10.1371/journal.pone.0135555 · Cited by 49 · see citing works
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Lung disease manifestations in Down syndrome
Danopoulos, S., Deutsch, G. H., Dumortier, C., Mariani, T. J., & Alam, D. A. (2021) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00434.2020 · Cited by 49 · see citing works
Neurodevelopment in Down syndrome: Concordance in humans and models
Klein, J. A., & Haydar, T. F. (2022) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2022.941855 · Cited by 47 · see citing works
“A significant increase in astrocytes differentiated from trisomic iPSCs has been reported many times (Briggs et al., 2013; Chen et al., 2014; Hibaoui et al., 2014; Real et al., 2018; Mollo et al., 2021).”
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Basal Forebrain Cholinergic Neurons: Linking Down Syndrome and Alzheimer’s Disease
Martinez, J. L., Zammit, M. D., West, N. R., Christian, B. T., & Bhattacharyya, A. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.703876 · Cited by 45 · see citing works
Stem and progenitor cell dysfunction in human trisomies
Liu, B., Filippi, S. L., Roy, A., & Roberts, I. A. G. (2014) · EMBO Reports · doi:10.15252/embr.201439583 · Cited by 42 · see citing works
Preferential amplification of a human mitochondrial DNA deletion in vitro and in vivo
Russell, O. M., Fruh, I., Rai, P. K., Marcellin, D., Doll, T., Reeve, A. K., Germain, M., Bastien, J., Rygiel, K. A., Cerino, R., et al. (2018) · Scientific Reports · doi:10.1038/s41598-018-20064-2 · Cited by 43 · see citing works
Human iPSC application in Alzheimer’s disease and tau-related neurodegenerative diseases
TCW, J. (2019) · Neuroscience Letters · doi:10.1016/j.neulet.2019.01.043 · Cited by 39 · see citing works
Modeling cancer using patient-derived induced pluripotent stem cells to understand development of childhood malignancies
Navarro, A. M., Susanto, E., Falk, A., & Wilhelm, M. (2018) · Cell Death Discovery · doi:10.1038/s41420-017-0009-2 · Cited by 38 · see citing works
Cellular reprogramming for understanding and treating human disease
Kanherkar, R. R., Bhatia‐Dey, N., Makarev, E., & Csoka, A. B. (2014) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2014.00067 · Cited by 37 · see citing works
The Challenging Pathway of Treatment for Neurogenesis Impairment in Down Syndrome: Achievements and Perspectives
Stagni, F., & Bartesaghi, R. (2022) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2022.903729 · Cited by 31 · see citing works
A human isogenic iPSC-derived cell line panel identifies major regulators of aberrant astrocyte proliferation in Down syndrome
Kawatani, K., Nambara, T., Nawa, N., Yoshimatsu, H., Kusakabe, H., Hirata, K., Tanave, A., Sumiyama, K., Banno, K., Taniguchi, H., et al. (2021) · Communications Biology · doi:10.1038/s42003-021-02242-7 · Cited by 34 · see citing works
Identification of a miRNA multi-targeting therapeutic strategy in glioblastoma
Bassot, A., Dragic, H., Haddad, S. A., Moindrot, L., Odouard, S., Corlazzoli, F., Marinari, E., Bomane, A., Brassens, A., Marteyn, A., et al. (2023) · Cell Death and Disease · doi:10.1038/s41419-023-06117-z · Cited by 35 · see citing works
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Identification and characterization of the lncRNA signature associated with overall survival in patients with neuroblastoma
Sathipati, S. Y., Sahu, D., Huang, H., Lin, Y.-C., & Ho, S. (2019) · Scientific Reports · doi:10.1038/s41598-019-41553-y · Cited by 34 · see citing works
Cellular senescence and premature aging in Down Syndrome
Peng, L., Baradar, A. A., Aguado, J., & Wolvetang, E. J. (2023) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2023.111824 · Cited by 34 · see citing works
Down syndrome is an oxidative phosphorylation disorder
Bayona‐Bafaluy, M. P., Garrido-Pérez, N., Meade, P., Iglesias, E., Jiménez-Salvador, I., Montoya, J., Martínez‐Cué, C., & Ruiz‐Pesini, E. (2021) · Redox Biology · doi:10.1016/j.redox.2021.101871 · Cited by 33 · see citing works
APP and DYRK1A regulate axonal and synaptic vesicle protein networks and mediate Alzheimer’s pathology in trisomy 21 neurons
Wu, C.-I., Vinton, E. A., Pearse, R. V., Heo, K., Aylward, A. J., Hsieh, Y., Bi, Y., Adeleye, S., Fancher, S. B., Duong, D. M., et al. (2022) · Molecular Psychiatry · doi:10.1038/s41380-022-01454-5 · Cited by 33 · see citing works
Meta-analysis of transcriptomic data reveals clusters of consistently deregulated gene and disease ontologies in Down syndrome
Toma, I. D., Sierra, C., & Dierssen, M. (2021) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1009317 · Cited by 32 · see citing works
Induced pluripotent stem cells as a cellular model for studying Down Syndrome
Brigida, A., & Siniscalco, D. (2016) · Journal of Stem Cells and Regenerative Medicine · doi:10.46582/jsrm.1202009 · Cited by 20 · see citing works
Leucettinib-21, a DYRK1A Kinase Inhibitor as Clinical Drug Candidate for Alzheimer’s Disease and Down Syndrome
Meijer, L., Chrétien, E., & Ravel, D. (2024) · Journal of Alzheimer s Disease · doi:10.3233/jad-240078 · Cited by 30 · see citing works
A new era of disease modeling and drug discovery using induced pluripotent stem cells
Suh, W. (2016) · Archives of Pharmacal Research · doi:10.1007/s12272-016-0871-0 · Cited by 29 · see citing works
Human Trisomic iPSCs from Down Syndrome Fibroblasts Manifest Mitochondrial Alterations Early during Neuronal Differentiation
Mollo, N., Esposito, M., Aurilia, M., Scognamiglio, R., Accarino, R., Bonfiglio, F., Cicatiello, R., Charalambous, M., Procaccini, C., Micillo, T., et al. (2021) · Biology · doi:10.3390/biology10070609 · Cited by 29 · see citing works
Autonomous trisomic rescue of Down syndrome cells
Inoue, M., Kajiwara, K., Yamaguchi, A., Kiyono, T., Samura, O., Akutsu, H., Sago, H., Okamoto, A., & Umezawa, A. (2019) · Laboratory Investigation · doi:10.1038/s41374-019-0230-0 · Cited by 29 · see citing works
Consequences of trisomy 21 for brain development in Down syndrome
Russo, M. L., Sousa, A. M. M., & Bhattacharyya, A. (2024) · Nature Reviews Neuroscience · doi:10.1038/s41583-024-00866-2 · Cited by 28 · see citing works
The Use of Induced Pluripotent Stem Cell Technology to Advance Autism Research and Treatment
Acab, A., & Muotri, A. (2015) · Neurotherapeutics · doi:10.1007/s13311-015-0354-x · Cited by 31 · see citing works
Allele-Specific Biased Expression of the CNTN6 Gene in iPS Cell-Derived Neurons from a Patient with Intellectual Disability and 3p26.3 Microduplication Involving the CNTN6 Gene
Gridina, M. M., Matveeva, N. M., Fishman, V., Menzorov, A. G., Kizilova, H. A., Beregovoy, N. A., Kovrigin, I. I., Pristyazhnyuk, I. E., Oscorbin, I. P., Филипенко, М. Л., et al. (2018) · Molecular Neurobiology · doi:10.1007/s12035-017-0851-5 · Cited by 28 · see citing works
Cerebal overinhibition could be the basis for the high prevalence of epilepsy in persons with Down syndrome
Araújo, B. H. S., Torres, L. B., & Guilhoto, L. M. D. F. F. (2015) · Epilepsy & Behavior · doi:10.1016/j.yebeh.2015.10.004 · Cited by 27 · see citing works
Gene expression dysregulation domains are not a specific feature of Down syndrome
Ahlfors, H., Anyanwu, N., Pakanavicius, E., Dinischiotu, N., Lana‐Elola, E., Watson-Scales, S., Tosh, J., Wiseman, F. K., Briscoe, J., Page, K. M., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-10129-9 · Cited by 25 · see citing works
Challenges and Opportunities for Translation of Therapies to Improve Cognition in Down Syndrome
Lee, S. E., Duran-Martinez, M., Khantsis, S., Bianchi, D., & Guedj, F. (2019) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2019.10.001 · Cited by 23 · see citing works
Dysfunctions of mitochondria in close association with strong perturbation of long noncoding RNAs expression in down syndrome
Qiu, J., Liu, Y.-N., Ren, Z., & Yan, J. (2017) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2017.09.017 · Cited by 23 · see citing works
The tweety Gene Family: From Embryo to Disease
Nalamalapu, R., Yue, M., Stone, A. R., Murphy, S. H., & Saha, M. S. (2021) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2021.672511 · Cited by 21 · see citing works
Impaired Brain Mitochondrial Bioenergetics in the Ts65Dn Mouse Model of Down Syndrome Is Restored by Neonatal Treatment with the Polyphenol 7,8-Dihydroxyflavone
Valenti, D., Stagni, F., Emili, M., Guidi, S., Bartesaghi, R., & Vacca, R. A. (2021) · Antioxidants · doi:10.3390/antiox11010062 · Cited by 22 · see citing works
Neurological diseases at the blood-brain barrier: Stemming new scientific paradigms using patient-derived induced pluripotent cells
Page, S., Patel, R., Raut, S., & Al-Ahmad, A. J. (2018) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2018.12.009 · Cited by 22 · see citing works
Trisomic rescue via allele-specific multiple chromosome cleavage using CRISPR-Cas9 in trisomy 21 cells
Hashizume, R., Wakita, S., Sawada, H., Takebayashi, S., Kitabatake, Y., Miyagawa, Y., HIROKAWA, Y. S., Imai, H., & Kurahashi, H. (2025) · PNAS Nexus · doi:10.1093/pnasnexus/pgaf022 · Cited by 21 · see citing works
Understanding the genetic mechanisms and cognitive impairments in Down syndrome: towards a holistic approach
Abukhaled, Y., Hatab, K., Awadhalla, M., & Hamdan, H. (2023) · Journal of Neurology · doi:10.1007/s00415-023-11890-0 · Cited by 21 · see citing works
Modeling Down syndrome in cells: From stem cells to organoids
Gough, G., O’Brien, N. L., Alić, I., Goh, P. A., Yeap, Y. J., Groet, J., Nižetić, D., & Murray, A. (2019) · Progress in brain research · doi:10.1016/bs.pbr.2019.10.003 · Cited by 20 · see citing works
Rethinking intellectual disability from neuro- to astro-pathology.
Fernández-Blanco, Á., & Dierssen, M. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21239039 · Cited by 19 · see citing works
Transition from Animal-Based to Human Induced Pluripotent Stem Cells (iPSCs)-Based Models of Neurodevelopmental Disorders: Opportunities and Challenges
Guerreiro, S. R., & Maciel, P. (2023) · Cells · doi:10.3390/cells12040538 · Cited by 20 · see citing works
Generation of kisspeptin-responsive GnRH neurons from human pluripotent stem cells
Poliandri, A., Miller, D. C., Howard, S. R., Nobles, M., Ruiz‐Babot, G., Harmer, S. C., Tinker, A., McKay, T. R., Guasti, L., & Dunkel, L. (2017) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2017.02.030 · Cited by 19 · see citing works
4-Phenylbutyrate ameliorates apoptotic neural cell death in Down syndrome by reducing protein aggregates
Hirata, K., Nambara, T., Kawatani, K., Nawa, N., Yoshimatsu, H., Kusakabe, H., Banno, K., Nishimura, K., Ohtaka, M., Nakanishi, M., et al. (2020) · Scientific Reports · doi:10.1038/s41598-020-70362-x · Cited by 17 · see citing works
Cell models for Down syndrome-Alzheimer’s disease research
Wu, Y., West, N. R., Bhattacharyya, A., & Wiseman, F. K. (2022) · Neuronal Signaling · doi:10.1042/ns20210054 · Cited by 17 · see citing works
In vivo1H MRS study in microlitre voxels in the hippocampus of a mouse model of Down syndrome at 11.7 T
Santin, M. D., Valabrègue, R., Rivals, I., Pénager, R., Paquin, R., Dauphinot, L., Albac, C., Delatour, B., & Potier, M. (2014) · NMR in Biomedicine · doi:10.1002/nbm.3155 · Cited by 17 · see citing works
Multiplying embryos: experimental monozygotic polyembryony in mammals and its uses
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Research Article
Hibaoui, Y., Grad, I., Letourneau, A., Sailani, M. R., Dahoun, S., Federico, A., Gimelli, S., Pelte, M. F., Stylianos, E., & Feki, A. (2016)
Self-citation
Modeling neurogenesis impairment in down syndrome with induced pluripotent stem cells from Trisomy 21 amniotic fluid cells
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Generation of two induced pluripotent stem cell lines from patients with Down syndrome
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Deficits in human trisomy 21 iPSCs and neurons
Weick, J. P., Held, D. L., Bonadurer, G. F., Doers, M. E., Liu, Y., Maguire, C., Clark, A., Knackert, J. A., Molinarolo, K., Musser, M., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1216575110 · Cited by 205 · see citing works
Autonomous trisomic rescue of Down syndrome cells
Inoue, M., Kajiwara, K., Yamaguchi, A., Kiyono, T., Samura, O., Akutsu, H., Sago, H., Okamoto, A., & Umezawa, A. (2019) · Laboratory Investigation · doi:10.1038/s41374-019-0230-0 · Cited by 29 · see citing works

Authors: Hibaoui, Y., Grad, I., Letourneau, A., Sailani, M. R., Dahoun, S., Santoni, F. A., Gimelli, S., Guipponi, M., Pelte, M. F., Béna, F., Antonarakis, S. E., & Feki, A.
Affiliations: University of Geneva (CH)
University Hospital of Geneva (CH)
Corresponding author: Antonarakis, Stylianos E
ORCID: Hibaoui, Youssef
Grad, Iwona
Sailani, M Reza
Santoni, Federico A
Guipponi, Michel
Antonarakis, Stylianos E
Venue: EMBO Molecular Medicine
Publisher: Springer Science and Business Media LLC
Published: 2013-12-27
Volume: 6
Issue: 2
Pages: 259-277
ISSN: 1757-4676 (ISSN-L)
1757-4684
DOI: 10.1002/emmm.201302848
PMC: PMC3927959
OpenAlex: W2169926950
Cited by: 170
References: 73
Citations by year: 2026: 4 · 2025: 11 · 2024: 9 · 2023: 10 · 2022: 20 · 2021: 20 · 2020: 11 · 2019: 20 · 2018: 13 · 2017: 12 · 2016: 13 · 2015: 16 · 2014: 11
FWCI: 13.63
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/3.0/ (tdm)
creativecommons.org/licenses/by/3.0/ (vor)
Locations: EMBO Molecular Medicine (publishedVersion, cc-by)
Europe PMC (PubMed Central) (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
SERVAL (Université de Lausanne) (publishedVersion, cc-by)
Archive ouverte UNIGE (University of Geneva) (publishedVersion, other-oa)
IRIS (submittedVersion, cc-by)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
Funders: Ernest Boninchi Fondation
Swiss National Science Foundation
European Research Council
Topics: Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
Keywords: Down syndrome, induced pluripotent stem cells, monozygotic twins, neurodevelopmental defects, neuronal differentiation, teratoma, neurogenesis, DYRK1A, shRNA knockdown, pharmacological correction, iPSC-derived neurons, oligodendrocytes, astrocytes
MeSH terms: Dyrk Kinases, Animals, Cell Differentiation, Down Syndrome, Humans, Models, Biological, Neurons, Protein-Tyrosine Kinases, Twins, Monozygotic, Genome, Human, Mice, SCID, Mice, Inbred NOD, Apoptosis, Protein Serine-Threonine Kinases, Cell Proliferation, Mice, Neurogenesis, Induced Pluripotent Stem Cells, Neural Stem Cells, Transcriptome, Gene Ontology

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Modelling and rescuing neurodevelopmental defect of Down syndrome using induced pluripotent stem cells from monozygotic twins discordant for trisomy 21

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