Cell-type-specific profiling of human cellular models of fragile X syndrome reveal PI3K-dependent defects in translation and neurogenesis.
Biological Assay
Cell Differentiation
Cell Lineage
/ genetics
Cell Proliferation
Class I Phosphatidylinositol 3-Kinases
/ antagonists & inhibitors
Fragile X Mental Retardation Protein
/ genetics
Fragile X Syndrome
/ genetics
Gene Expression Regulation, Developmental
Humans
Imidazoles
/ pharmacology
Induced Pluripotent Stem Cells
/ drug effects
Models, Biological
Morpholines
/ pharmacology
Neural Stem Cells
/ drug effects
Neurogenesis
/ genetics
Organoids
/ drug effects
Phosphoinositide-3 Kinase Inhibitors
/ pharmacology
Piperazines
/ pharmacology
Primary Cell Culture
Protein Biosynthesis
Pyrimidinones
/ pharmacology
RNA, Messenger
/ genetics
Signal Transduction
FMRP
Fragile X syndrome
autism
flow cytometry
iPSCs
neural stem cells
neurogenesis
protein synthesis
translation
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
13 04 2021
13 04 2021
Historique:
received:
19
02
2020
revised:
08
03
2021
accepted:
23
03
2021
entrez:
14
4
2021
pubmed:
15
4
2021
medline:
15
2
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33852833
pii: S2211-1247(21)00305-3
doi: 10.1016/j.celrep.2021.108991
pmc: PMC8133829
mid: NIHMS1693707
pii:
doi:
Substances chimiques
FMR1 protein, human
0
Imidazoles
0
Morpholines
0
PF-4708671
0
Phosphoinositide-3 Kinase Inhibitors
0
Piperazines
0
Pyrimidinones
0
RNA, Messenger
0
TGX 221
0
Fragile X Mental Retardation Protein
139135-51-6
Class I Phosphatidylinositol 3-Kinases
EC 2.7.1.137
PIK3CB protein, human
EC 2.7.1.137
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
108991Subventions
Organisme : NICHD NIH HHS
ID : P50 HD104458
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM133385
Pays : United States
Organisme : NICHD NIH HHS
ID : R01 HD084215
Pays : United States
Organisme : NINDS NIH HHS
ID : R35 NS111602
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS115660
Pays : United States
Organisme : NINDS NIH HHS
ID : K08 NS087121
Pays : United States
Organisme : NICHD NIH HHS
ID : U54 HD082013
Pays : United States
Informations de copyright
Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
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