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

Jason W. Adams; Annabelle Vinokur; Janaína S. de Souza; Charles Austria; Bruno S. Guerra; Roberto H. Herai; Karl J. Wahlin; Alysson R. Muotri

Cell Reports (Mar 2024)

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

Jason W. Adams,
Annabelle Vinokur,
Janaína S. de Souza,
Charles Austria,
Bruno S. Guerra,
Roberto H. Herai,
Karl J. Wahlin,
Alysson R. Muotri

Affiliations

Jason W. Adams: Department of Pediatrics/Rady Children’s Hospital, Department of Cellular & Molecular Medicine, University of California, San Diego School of Medicine, La Jolla, CA 92037, USA; Department of Neurosciences, University of California, San Diego School of Medicine, La Jolla, CA 92093, USA; Center for Academic Research and Training in Anthropogeny, University of California, San Diego, La Jolla, CA 92093, USA
Annabelle Vinokur: Department of Pediatrics/Rady Children’s Hospital, Department of Cellular & Molecular Medicine, University of California, San Diego School of Medicine, La Jolla, CA 92037, USA
Janaína S. de Souza: Department of Pediatrics/Rady Children’s Hospital, Department of Cellular & Molecular Medicine, University of California, San Diego School of Medicine, La Jolla, CA 92037, USA
Charles Austria: Department of Pediatrics/Rady Children’s Hospital, Department of Cellular & Molecular Medicine, University of California, San Diego School of Medicine, La Jolla, CA 92037, USA
Bruno S. Guerra: Department of Pediatrics/Rady Children’s Hospital, Department of Cellular & Molecular Medicine, University of California, San Diego School of Medicine, La Jolla, CA 92037, USA; Experimental Multiuser Laboratory, Pontifícia Universidade Católica do Paraná, Curitiba, PR 80215-901, Brazil
Roberto H. Herai: Department of Pediatrics/Rady Children’s Hospital, Department of Cellular & Molecular Medicine, University of California, San Diego School of Medicine, La Jolla, CA 92037, USA; Experimental Multiuser Laboratory, Pontifícia Universidade Católica do Paraná, Curitiba, PR 80215-901, Brazil
Karl J. Wahlin: Shiley Eye Institute, University of California, San Diego, La Jolla, CA 92093, USA
Alysson R. Muotri: Department of Pediatrics/Rady Children’s Hospital, Department of Cellular & Molecular Medicine, University of California, San Diego School of Medicine, La Jolla, CA 92037, USA; Center for Academic Research and Training in Anthropogeny, University of California, San Diego, La Jolla, CA 92093, USA; Corresponding author

Journal volume & issue: Vol. 43, no. 3
p. 113867

Abstract

Read online

Summary: Individuals with Williams syndrome (WS), a neurodevelopmental disorder caused by hemizygous loss of 26–28 genes at 7q11.23, characteristically portray a hypersocial phenotype. Copy-number variations and mutations in one of these genes, GTF2I, are associated with altered sociality and are proposed to underlie hypersociality in 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, are differentiated from CRISPR-Cas9-edited GTF2I-knockout (GTF2I-KO) pluripotent stem cells to investigate the role of GTF2I in human neurodevelopment. GTF2I-KO progenitors exhibit increased proliferation and cell-cycle alterations. Cortical organoids and neurons demonstrate increased cell death and synaptic dysregulation, including synaptic structural dysfunction and decreased electrophysiological activity on a multielectrode array. Our findings suggest that changes in synaptic circuit integrity may be a prominent mediator of the link between alterations in GTF2I and variation in the phenotypic expression of human sociality.

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

About the journal

Abstract

Keywords