Altered cortical Cytoarchitecture in the Fmr1 knockout mouse

Lee, Frankie H. F.; Lai, Tony W.; Su, Ping; Liu, Fang

doi:10.1186/s13041-019-0478-8

Cited by 36 publications

(30 citation statements)

References 73 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We found, in 3D cortical organoids derived from FMRP-KO hiPSCs, a significant increase in cortical organoid size, a reduction in neuronal marker MAP2 and an increase in astrocyte reactivity. The increase in GFAP staining was observed also in the 2D neural differentiation system and resembles what reported in primary glial cells isolated from Fmr1 KO mice [45]. Astrocytes are well recognized as active players in the neurobiology of FXS and involved in the correct development and maturation of hippocampal synapses [61][62][63].…”

Section: Discussionsupporting

confidence: 80%

Novel fragile X syndrome 2D and 3D brain models based on human isogenic FMRP-KO iPSCs

Brighi

Salaris

Soloperto

et al. 2020

Preprint

View full text Add to dashboard Cite

Fragile X syndrome (FXS) is a neurodevelopmental disorder, characterized by intellectual disability and sensory deficits, caused by epigenetic silencing of the FMR1 gene and subsequent loss of its protein product, fragile X mental retardation protein (FMRP). Delays in synaptic and neuronal development in the cortex have been reported in FXS mouse models, however, the main goal of translating lab research into pharmacological treatments in clinical trials has been so far largely unsuccessful, leaving FXS a still incurable disease. Here, we generated 2D and 3D in vitro human FXS model systems based on isogenic FMR1 knock-out mutant and wild-type human induced pluripotent stem cell (hiPSC) lines. Phenotypical and functional characterization of cortical neurons derived from FMRP-deficient hiPSCs display altered gene expression and impaired differentiation when compared with the healthy counterpart. FXS cortical cultures show increased proliferation of GFAP positive cells, likely astrocytes, increased spontaneous network activity and depolarizing GABAergic transmission. Cortical brain organoid models show increased proliferation of glial cells, and bigger organoid size. Our findings demonstrate that FMRP is required to correctly support neuronal and glial cell proliferation, and to set the correct excitation/inhibition ratio in human brain development.

show abstract

Section: Discussionsupporting

confidence: 80%

Novel fragile X syndrome 2D and 3D brain models based on human isogenic FMRP-KO iPSCs

Brighi

Salaris

Soloperto

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…S6K activity induces differentiation in pluripotent human embryonic stem cells [54], while knockdown of 4E-BP2, the major 4E-BP expressed in the brain, is sufficient to induce NPCs differentiation [61]. Taken together, our results can explain how altered proliferation and differentiation of NPCs [18,62] may lead to an abnormal cortical cytoarchitecture seen in Fmr1 KO mouse brain [63].…”

Section: Discussionmentioning

confidence: 68%

Identification of FMRP target mRNAs in the developmental brain: FMRP might coordinate Ras/MAPK, Wnt/β-catenin, and mTOR signaling during corticogenesis

et al. 2020

View full text Add to dashboard Cite

Corticogenesis is one of the most critical and complicated processes during embryonic brain development. Any slight impairment in corticogenesis could cause neurodevelopmental disorders such as Fragile X syndrome (FXS), of which symptoms contain intellectual disability (ID) and autism spectrum disorder (ASD). Fragile X mental retardation protein (FMRP), an RNA-binding protein responsible for FXS, shows strong expression in neural stem/precursor cells (NPCs) during corticogenesis, although its function during brain development remains largely unknown. In this study, we attempted to identify the FMRP target mRNAs in the cortical primordium using RNA immunoprecipitation sequencing analysis in the mouse embryonic brain. We identified 865 candidate genes as targets of FMRP involving 126 and 118 genes overlapped with ID and ASD-associated genes, respectively. These overlapped genes were enriched with those related to chromatin/chromosome organization and histone modifications, suggesting the involvement of FMRP in epigenetic regulation. We further identified a common set of 17 FMRP “core” target genes involved in neurogenesis/FXS/ID/ASD, containing factors associated with Ras/mitogen-activated protein kinase, Wnt/β-catenin, and mammalian target of rapamycin (mTOR) pathways. We indeed showed overactivation of mTOR signaling via an increase in mTOR phosphorylation in the Fmr1 knockout (Fmr1 KO) neocortex. Our results provide further insight into the critical roles of FMRP in the developing brain, where dysfunction of FMRP may influence the regulation of its mRNA targets affecting signaling pathways and epigenetic modifications.

show abstract

“…Indeed, astrocytes, oligodendrocyte precursor cells, and microglia express FMRP in a brain structure and development-dependent manner 23 . FMRP-depleted astrocytes are more reactive 24 , and their deficits alone may account for some of the phenotypes seen in Fragile X neurons particularly during development [25][26][27][28] .…”

Section: Introductionmentioning

confidence: 99%

Single Cell Transcriptomics Reveals Dysregulated Cellular and Molecular Networks in a Fragile X Syndrome model

Donnard

Shu

Garber

2020

Preprint

View full text Add to dashboard Cite

Despite advances in understanding the pathophysiology of Fragile X syndrome (FXS), its molecular bases are still poorly understood. Whole brain tissue expression profiles have proved surprisingly uninformative. We applied single cell RNA sequencing to profile a FXS mouse model. We found that FXS results in a highly cell type specific effect and it is strongest among different neuronal types. We detected a downregulation of mRNAs bound by FMRP and this effect is prominent in neurons. Metabolic pathways including translation are significantly upregulated across all cell types with the notable exception of excitatory neurons. These effects point to a potential difference in the activity of mTOR pathways, and together with other dysregulated pathways suggest an excitatory-inhibitory imbalance in the FXS cortex which is exacerbated by astrocytes. Our data demonstrate the cell-type specific complexity of FXS and provide a resource for interrogating the biological basis of this disorder.

show abstract

Altered cortical Cytoarchitecture in the Fmr1 knockout mouse

Cited by 36 publications

References 73 publications

Novel fragile X syndrome 2D and 3D brain models based on human isogenic FMRP-KO iPSCs

Novel fragile X syndrome 2D and 3D brain models based on human isogenic FMRP-KO iPSCs

Identification of FMRP target mRNAs in the developmental brain: FMRP might coordinate Ras/MAPK, Wnt/β-catenin, and mTOR signaling during corticogenesis

Single Cell Transcriptomics Reveals Dysregulated Cellular and Molecular Networks in a Fragile X Syndrome model

Contact Info

Product

Resources

About