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Keywords:

  • disease modelling;
  • Down syndrome;
  • DYRK1A ;
  • induced pluripotent stem cells;
  • neurodevelopment

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.

Synopsis

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The generation and characterization of iPSCs from monozygotic twins discordant for trisomy 21 allows studying Down syndrome early embryonic development and pathogenesis. DYRK1A inhibition is further shown with therapeutic potentials for DS patients.

  • A cellular model of the neurodevelopmental defects in Down syndrome using iPSCs derived from monozygotic twins discordant for trisomy 21 has been created.
  • The transcriptional signature of DS-iPSCs has been established.
  • DS-iPSCs were shown to exhibit a reduced neurogenesis and increased astroglial and oligodendroglial cell population upon neural induction into NPCs and neuronal differentiation.
  • Both proliferation deficit and increased apoptosis were found in NPCs along with a reduced dendritic and synaptic development in neurons derived from DS-iPSCs.
  • Targeting DYRK1A gene expression and protein activity using shRNA silencing or pharmacological means was shown to correct these defects likely through REST/NRSF, WNT and NOTCH signaling.