Cell-type-specific profiling of human cellular models of fragile X syndrome reveal PI3K-dependent defects in translation and neurogenesis

• Type of Material: Article
• Authors: Nisha Raj, Emory University; Zachary McEachin, Emory University; William Harousseau, Emory University; Ying Zhou, Emory University; Feiran Zhang, Emory University; Meagan E Merritt-Garza, Emory University; Matthew Taliaferro, University of Colorado Anschutz; Magdalena Kalinowska, New York University; Samuele G Marro, Icahn School of Medicine at Mount Sinai; Chadwick Hales, Emory University; Elizabeth Berry-Kravis, Rush University; Marisol W Wolf-Ochoa, UC Davis School of Medicine; Veronica Martinez-Cerdeno, UC Davis School of Medicine; Marius Wernig, Stanford University; Lu Chen, Stanford University; Eric Klann, NYU; Stephen Warren, Emory University; Peng Jin, Emory University; Zhexing Wen, Emory University; Gary Bassell, Emory University
• Language: English
• Date: 2021-04-13
• Publisher: CELL PRESS
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2021 The Author(s).
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.celrep.2021.108991
• Title of Journal or Parent Work: CELL REPORTS
• Volume: 35
• Issue: 2
• Start Page: 108991
• End Page: 108991
• Grant/Funding Information: This work was largely supported by a NICHD Fragile X Center project grant 1U54HD082013–01 (G.J.B) and, more recently, by 1P50HD104458 (G.J.B). This research project was supported in part by the Emory University Integrated Cellular Imaging Microscopy Core. C.M.H was supported by a National Institute of Neurological Disorders and Stroke award (K08-NS087121). J.M.T was supported by the RNA Bioscience Initiative at the University of Colorado Anschutz Medical Campus and the Webb-Waring Early Career Investigator Award from the Boettcher Foundation (AWD-182937).
• Keywords: NEURAL STEM-CELLS; MOUSE MODEL; NEURONS; GENERATION; Life Sciences & Biomedicine; DYSREGULATION; Science & Technology; Cell Biology; GENE; EXPRESSION; PROTEIN-SYNTHESIS

Abstract

Transcriptional silencing of the FMR1 gene in fragile X syndrome (FXS) leads to the loss of the RNA-binding protein FMRP. In addition to regulating mRNA translation and protein synthesis, emerging evidence suggests that FMRP acts to coordinate proliferation and differentiation during early neural development. However, whether loss of FMRP-mediated translational control is related to impaired cell fate specification in the developing human brain remains unknown. Here, we use human patient induced pluripotent stem cell (iPSC)-derived neural progenitor cells and organoids to model neurogenesis in FXS. We developed a high-throughput, in vitro assay that allows for the simultaneous quantification of protein synthesis and proliferation within defined neural subpopulations. We demonstrate that abnormal protein synthesis in FXS is coupled to altered cellular decisions to favor proliferative over neurogenic cell fates during early development. Furthermore, pharmacologic inhibition of elevated phosphoinositide 3-kinase (PI3K) signaling corrects both excess protein synthesis and cell proliferation in a subset of patient neural cells.