GSE252761 Loss of GTF2I promotes neuronal apoptosis and synaptic reduction in human cellular models of neurodevelopment

Contributors : Jason W Adams ; Annabelle Vinokur ; Janaina S de Souza ; Charles Austria ; Bruno S Guerra ; Roberto H Herai ; Karl J Wahlin ; Alysson R MuotriSeries Type : Expression profiling by high throughput sequencingOrganism : Homo sapiensIndividuals with Williams syndrome (WS), a multisystemic neurodevelopmental disorder, characteristically portray a hypersocial phenotype. WS is caused by the hemizygous loss of 26-28 genes at chromosomal locus 7q11.23, one of which is GTF2I. Copy number variations and mutations in GTF2I are associated with altered sociality and have been proposed to underlie the hypersocial expression of WS. However, the contribution of GTF2I to human neurodevelopment remains poorly understood. Here, human cellular models of neurodevelopment, including neural progenitors, neurons, and three-dimensional cortical organoids, were differentiated from CRISPR-Ca9-edited GTF2I-knockout (GTF2I-KO) pluripotent stem cells (hiPSCs) to investigate the role of GTF2I in human neurodevelopment. Compared to controls, GTF2I-KO progenitors exhibited an increased proliferation rate and an altered cell cycle profile. Cortical organoids and neurons demonstrated increased cell death and synaptic dysregulation, including synaptic structural dysfunction and decreased electrophysiological activity on a multi-electrode array. Overall, our findings suggest that changes in synaptic circuit integrity may be a prominent mediator of the link between alterations in GTF2I and variati...
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Expression profiling by high throughput sequencing Homo sapiens Source Type: research