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

Cell Rep. 2021 Apr 13;35(2):108991. doi: 10.1016/j.celrep.2021.108991.


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.

Keywords: FMRP; Fragile X syndrome; autism; flow cytometry; iPSCs; neural stem cells; neurogenesis; protein synthesis; translation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biological Assay
  • Cell Differentiation
  • Cell Lineage / genetics
  • Cell Proliferation
  • Class I Phosphatidylinositol 3-Kinases / antagonists & inhibitors
  • Class I Phosphatidylinositol 3-Kinases / genetics*
  • Class I Phosphatidylinositol 3-Kinases / metabolism
  • Fragile X Mental Retardation Protein / genetics*
  • Fragile X Mental Retardation Protein / metabolism
  • Fragile X Syndrome / genetics*
  • Fragile X Syndrome / metabolism
  • Fragile X Syndrome / pathology
  • Gene Expression Regulation, Developmental
  • Humans
  • Imidazoles / pharmacology
  • Induced Pluripotent Stem Cells / drug effects
  • Induced Pluripotent Stem Cells / metabolism*
  • Induced Pluripotent Stem Cells / pathology
  • Models, Biological
  • Morpholines / pharmacology
  • Neural Stem Cells / drug effects
  • Neural Stem Cells / metabolism*
  • Neural Stem Cells / pathology
  • Neurogenesis / genetics
  • Organoids / drug effects
  • Organoids / metabolism
  • Organoids / pathology
  • Phosphoinositide-3 Kinase Inhibitors / pharmacology
  • Piperazines / pharmacology
  • Primary Cell Culture
  • Protein Biosynthesis
  • Pyrimidinones / pharmacology
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Signal Transduction


  • FMR1 protein, human
  • Imidazoles
  • Morpholines
  • PF-4708671
  • Phosphoinositide-3 Kinase Inhibitors
  • Piperazines
  • Pyrimidinones
  • RNA, Messenger
  • TGX 221
  • Fragile X Mental Retardation Protein
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CB protein, human