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

Abstract

SUMMARY 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.

The Identification and Functional Analysis of mRNA Localizing to Centrosomes

“…Among the putative RNA targets of FMRP, several overlap with CPEB ( Costa et al, 2005 ; Udagawa et al, 2013 ). FMRP regulates mitotic progression in many tissues, as loss of Fmr1 leads to elevated rates of neural stem cell proliferation, resulting in impaired neurogenesis in Drosophila and, remarkably, in induced pluripotent stem cells (iPSCs) derived from FXS patients ( Callan et al, 2010 ; Raj et al, 2021 ).…”

Fmrp regulates neuronal balance in embryonic motor circuit formation

“…As Fmrp also plays crucial roles in the differentiation of neurons and glia (Luo et al, 2010; Edens et al, 2019; Doll et al, 2021; Raj et al, 2021), it is possible that the excess GABAergic cells in fmr1 mutants are not terminally differentiated and do not form synaptic connections. To address this possibility, we examined expression of the postsynaptic scaffold Gephyrin, which is crucial for the clustering and stabilization of GABAergic and glycinergic receptors (Essrich et al, 1998; Feng et al, 1998).…”

MolData, a molecular benchmark for disease and target based machine learning

“…They have the capability of screening 100 s to 1,000 s of compound plates a day [ 54 , 55 ], Sanford-Burnham Center for Chemical Genomics is a well stablished screening center working on multiple projects including NIH Molecular Libraries program (MLP) with applications on multiple diseases [ 56 , 57 ], NMMLSC is an screening center with capability of using high throughput flow cytometry to discover molecules as chemical probes for drug discovery [ 58 , 59 ], Emory University Molecular Libraries Screening Center with focus on Biological Discovery through Chemical Innovation and also molecular pathogenesis to global pandemics. [ 60 , 61 ], Tox21 which contains thousands of medicinal or environmental substances which is a collaboration between NCATS and national toxicology program. Tox21 is an ongoing project with yearly update [ 62 , 63 ], The Scripps Research Institute Molecular Screening Center is an automated center with projects on a variety of diseases like Alzheimer and cancer.…”

“…Emory University Molecular Libraries Screening Center with focus on Biological Discovery through Chemical Innovation and also molecular pathogenesis to global pandemics. [ 60 , 61 ],…”