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| Status |
Public on Jun 29, 2022 |
| Title |
Delayed maturation of Fragile X Syndrome GABAergic neurogenesis revealed by functional and single-cell gene expression analysis |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
FXS (Fragile X Syndrome), a leading monogenic cause of intellectual disability and autism spectrum disorder, is caused by an expansion of a CGG repeat in the 5′-UTR of the FMR1 (Fragile X Mental Retardation-1) gene.
While current studies of FXS have focused on the effects of Fragile X Mental Retardation Protein (FMRP) loss in excitatory neurons, evidence suggests that GABAergic inhibitory networks are also affected in FXS.
In this study, we developed a method to reproducibly derive GABAergic inhibitory neurons from multiple FXS and control human pluripotent stem cell lines (PSCs).
We found that compared to control, functional assays with microelectrode arrays and immunocytochemistry suggested a developmental delay in the maturing FXS inhibitory network that involves the GABA function switch.
The GABA function switch converts the GABAA channel’s role from depolarization to hyperpolarization and has profound effects on the developing brain.
To investigate the cause of this delay, we analyzed 14,400 single-cell transcriptomes from FXS and control PSC-derived GABAergic neuron cultures at early and late stages of neurogenesis.
Genes related to neuroblast proliferation were upregulated in FXS cells, while neuron-specific differentially expressed genes (DEGs) associated with action potential regulation, synaptic processes, and mitochondria function were downregulated in FXS cells.
In addition, autism-associated genes were overrepresented in the DEGs. Our analysis of inhibitory neuron development suggests that loss of FMRP is associated with delays in the GABAergic neurogenesis and maturation.
This observation suggests a novel direction for understanding the underlying disease mechanisms and may help to guide development of therapeutic interventions.
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| Overall design |
single cell RNAseq profiling from 3 FXS and 3 Control hPSC-derived GABAergic inhibitory neurons at 2 timepoints: day 22 and day 42-48 of differentiation
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| Contributor(s) |
Zhang A, Domissy A |
| Citation(s) |
35556144 |
| |
| Submission date |
Mar 08, 2022 |
| Last update date |
Jun 30, 2022 |
| Contact name |
Alain Domissy |
| Organization name |
The Scripps Research Institute
|
| Department |
Immunology
|
| Lab |
Computational Immunology Group
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| Street address |
10550 North Torrey Pines Road
|
| City |
La Jolla |
| State/province |
CA |
| ZIP/Postal code |
92037 |
| Country |
USA |
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| Platforms (1) |
| GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
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| Samples (14)
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| Relations |
| BioProject |
PRJNA814265 |
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