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

Details

Serval ID
serval:BIB_7387E90C888C
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Modelling and rescuing neurodevelopmental defect of Down syndrome using induced pluripotent stem cells from monozygotic twins discordant for trisomy 21
Journal
EMBO Mol Med
Author(s)
Hibaoui Y., Grad I., Letourneau A., Sailani M. R., Dahoun S., Santoni F. A., Gimelli S., Guipponi M., Pelte M. F., Bena F., Antonarakis S. E., Feki A.
ISSN
1757-4684 (Electronic)
ISSN-L
1757-4676
Publication state
Published
Issued date
02/2014
Volume
6
Number
2
Pages
259-77
Language
english
Notes
Hibaoui, Youssef
Grad, Iwona
Letourneau, Audrey
Sailani, M Reza
Dahoun, Sophie
Santoni, Federico A
Gimelli, Stefania
Guipponi, Michel
Pelte, Marie Francoise
Bena, Frederique
Antonarakis, Stylianos E
Feki, Anis
eng
Research Support, Non-U.S. Gov't
England
EMBO Mol Med. 2014 Feb;6(2):259-77. doi: 10.1002/emmm.201302848. Epub 2013 Dec 27.
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 1A (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.
Keywords
Animals, Apoptosis/genetics, Cell Differentiation/genetics, Cell Proliferation, Down Syndrome/genetics/*pathology/*therapy, Gene Ontology, Genome, Human/genetics, Humans, Induced Pluripotent Stem Cells/cytology/*transplantation, Mice, Mice, Inbred NOD, Mice, SCID, *Models, Biological, Neural Stem Cells/pathology, Neurogenesis/genetics, Neurons/metabolism/pathology, Protein-Serine-Threonine Kinases/antagonists & inhibitors/metabolism, Protein-Tyrosine Kinases/antagonists & inhibitors/metabolism, Transcriptome/genetics, Twins, Monozygotic/*genetics
Pubmed
Create date
20/05/2019 12:52
Last modification date
14/12/2019 6:26
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