title: Deficits in human trisomy 21 iPSCs and neurons.
abstract: Down syndrome (trisomy 21) is the most common genetic cause of intellectual disability, but the precise molecular mechanisms underlying impaired cognition remain unclear. Elucidation of these mechanisms has been hindered by the lack of a model system that contains full trisomy of chromosome 21 (Ts21) in a human genome that enables normal gene regulation. To overcome this limitation, we created Ts21-induced pluripotent stem cells (iPSCs) from two sets of Ts21 human fibroblasts. One of the fibroblast lines had low level mosaicism for Ts21 and yielded Ts21 iPSCs and an isogenic control that is disomic for human chromosome 21 (HSA21). Differentiation of all Ts21 iPSCs yielded similar numbers of neurons expressing markers characteristic of dorsal forebrain neurons that were functionally similar to controls. Expression profiling of Ts21 iPSCs and their neuronal derivatives revealed changes in HSA21 genes consistent with the presence of 50% more genetic material as well as changes in non-HSA21 genes that suggested compensatory responses to oxidative stress. Ts21 neurons displayed reduced synaptic activity, affecting excitatory and inhibitory synapses equally. Thus, Ts21 iPSCs and neurons display unique developmental defects that are consistent with cognitive deficits in individuals with Down syndrome and may enable discovery of the underlying causes of and treatments for this disorder.
authors.affiliation: Waisman Center, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53705, USA.
authors.forename: Jason P
authors.initials: JP
authors.lastname: Weick
authors.forename: Dustie L
authors.initials: DL
authors.lastname: Held
authors.forename: George F
authors.initials: GF
authors.lastname: Bonadurer
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Doers
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.forename: Chelsie
authors.initials: C
authors.lastname: Maguire
authors.forename: Aaron
authors.initials: A
authors.lastname: Clark
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Knackert
authors.forename: Katharine
authors.initials: K
authors.lastname: Molinarolo
authors.forename: Michael
authors.initials: M
authors.lastname: Musser
authors.forename: Lin
authors.initials: L
authors.lastname: Yao
authors.forename: Yingnan
authors.initials: Y
authors.lastname: Yin
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Lu
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Zhang
authors.forename: Su-Chun
authors.initials: SC
authors.lastname: Zhang
authors.forename: Anita
authors.initials: A
authors.lastname: Bhattacharyya
mesh_terms: D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics; D004314:Down Syndrome / Q000235:genetics*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D020869:Gene Expression Profiling; D005838:Genotype; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D009030:Mosaicism; D009474:Neurons / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D018384:Oxidative Stress; D018408:Patch-Clamp Techniques; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055366:Synaptic Potentials / Q000235:genetics
keywords: cerebral cortex; developmental disorders