A human forebrain organoid model of fragile X syndrome exhibits altered neurogenesis and highlights new treatment strategies

Kang, Yunhee; Zhou, Ying; Li, Yujing; Han, Yanfei; Xu, Jie; Niu, Weibo; Li, Ziyi; Liu, Shiying; Feng, Hao; Huang, Wen; Duan, Ranhui; Xu, Tianmin; Raj, Nisha; Zhang, Feiran; Dou, Jingtao; Xu, Chi; Wu, Hao; Bassell, Gary J.; Warren, Stephen T.; Allen, Emily G.; Jin, Peng; Wen, Zhexing

doi:10.1038/s41593-021-00913-6

Cited by 88 publications

(105 citation statements)

References 82 publications

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“…These results suggest a delayed or aberrant sensory neuronal development process resulting from the loss of FMRP. These observations are consistent with developmental delays suggested in mouse cortical neurons ( Tervonen et al, 2009 ; Saffary and Xie, 2011 ; Edens et al, 2019 ), as well as in human neurons and forebrain organoids ( Sunamura et al, 2018 ; Kang et al, 2021 ).…”

Section: Resultssupporting

confidence: 90%

Disrupted Association of Sensory Neurons With Enveloping Satellite Glial Cells in Fragile X Mouse Model

Avraham

Deng

Maschi

et al. 2022

Front. Mol. Neurosci.

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Among most prevalent deficits in individuals with Fragile X syndrome (FXS) is hypersensitivity to sensory stimuli and somatosensory alterations. Whether dysfunction in peripheral sensory system contributes to these deficits remains poorly understood. Satellite glial cells (SGCs), which envelop sensory neuron soma, play critical roles in regulating neuronal function and excitability. The potential contributions of SGCs to sensory deficits in FXS remain unexplored. Here we found major structural defects in sensory neuron-SGC association in the dorsal root ganglia (DRG), manifested by aberrant covering of the neuron and gaps between SGCs and the neuron along their contact surface. Single-cell RNAseq analyses demonstrated transcriptional changes in both neurons and SGCs, indicative of defects in neuronal maturation and altered SGC vesicular secretion. We validated these changes using fluorescence microscopy, qPCR, and high-resolution transmission electron microscopy (TEM) in combination with computational analyses using deep learning networks. These results revealed a disrupted neuron-glia association at the structural and functional levels. Given the well-established role for SGCs in regulating sensory neuron function, altered neuron-glia association may contribute to sensory deficits in FXS.

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Section: Resultssupporting

confidence: 90%

Disrupted Association of Sensory Neurons With Enveloping Satellite Glial Cells in Fragile X Mouse Model

Avraham

Deng

Maschi

et al. 2022

Front. Mol. Neurosci.

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“…The development of FMRP-tat peptides to reintroduce different FMRP segments to FMR1 KO neurons is a powerful tool for dissociating FMRPs function via direct protein-protein interactions from its canonical role in translational regulation (Zhan et al, 2020 ; Park et al, 2021 ). Finally, the development of novel FXS models—such as the FMR1 KO rat (Till et al, 2015 ; Golden et al, 2019 ; Auerbach et al, 2021 ) and FXS human derived iPS cells (Telias et al, 2013 ; Bhattacharyya and Zhao, 2016 ) and organoids (Kang et al, 2021 ), will help identify which phenotypes are most highly conserved across species and highlight new treatment strategies.…”

Section: Discussionmentioning

confidence: 99%

Hyperexcitability and Homeostasis in Fragile X Syndrome

Liu

Kumar

Tsai

et al. 2022

Front. Mol. Neurosci.

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Fragile X Syndrome (FXS) is a leading inherited cause of autism and intellectual disability, resulting from a mutation in the FMR1 gene and subsequent loss of its protein product FMRP. Despite this simple genetic origin, FXS is a phenotypically complex disorder with a range of physical and neurocognitive disruptions. While numerous molecular and cellular pathways are affected by FMRP loss, there is growing evidence that circuit hyperexcitability may be a common convergence point that can account for many of the wide-ranging phenotypes seen in FXS. The mechanisms for hyperexcitability in FXS include alterations to excitatory synaptic function and connectivity, reduced inhibitory neuron activity, as well as changes to ion channel expression and conductance. However, understanding the impact of FMR1 mutation on circuit function is complicated by the inherent plasticity in neural circuits, which display an array of homeostatic mechanisms to maintain activity near set levels. FMRP is also an important regulator of activity-dependent plasticity in the brain, meaning that dysregulated plasticity can be both a cause and consequence of hyperexcitable networks in FXS. This makes it difficult to separate the direct effects of FMR1 mutation from the myriad and pleiotropic compensatory changes associated with it, both of which are likely to contribute to FXS pathophysiology. Here we will: (1) review evidence for hyperexcitability and homeostatic plasticity phenotypes in FXS models, focusing on similarities/differences across brain regions, cell-types, and developmental time points; (2) examine how excitability and plasticity disruptions interact with each other to ultimately contribute to circuit dysfunction in FXS; and (3) discuss how these synaptic and circuit deficits contribute to disease-relevant behavioral phenotypes like epilepsy and sensory hypersensitivity. Through this discussion of where the current field stands, we aim to introduce perspectives moving forward in FXS research.

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“…Electrophysiology of hPSC-derived neurons is important for assessing how neuronal functions are disturbed in NDDs including changes in spontaneous neuronal activity, network activity, synaptic transmission, and calcium signaling [159,160]. In addition to the neuronal function, how mutations in NDD risk genes affect cortical neural progenitor proliferation and differentiation have been examined for several genes [150,[161][162][163]. These above-mentioned advances provide a robust platform to model NDDs and the diversity of tools used to analyze the impacts of NDD risk genes on neurodevelopment.…”

Section: Generation Of Brain Organoids From Hpscsmentioning

confidence: 99%

Harnessing the Power of Stem Cell Models to Study Shared Genetic Variants in Congenital Heart Diseases and Neurodevelopmental Disorders

Chang

Tchieu

2022

Cells

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Advances in human pluripotent stem cell (hPSC) technology allow one to deconstruct the human body into specific disease-relevant cell types or create functional units representing various organs. hPSC-based models present a unique opportunity for the study of co-occurring disorders where “cause and effect” can be addressed. Poor neurodevelopmental outcomes have been reported in children with congenital heart diseases (CHD). Intuitively, abnormal cardiac function or surgical intervention may stunt the developing brain, leading to neurodevelopmental disorders (NDD). However, recent work has uncovered several genetic variants within genes associated with the development of both the heart and brain that could also explain this co-occurrence. Given the scalability of hPSCs, straightforward genetic modification, and established differentiation strategies, it is now possible to investigate both CHD and NDD as independent events. We will first overview the potential for shared genetics in both heart and brain development. We will then summarize methods to differentiate both cardiac & neural cells and organoids from hPSCs that represent the developmental process of the heart and forebrain. Finally, we will highlight strategies to rapidly screen several genetic variants together to uncover potential phenotypes and how therapeutic advances could be achieved by hPSC-based models.

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A human forebrain organoid model of fragile X syndrome exhibits altered neurogenesis and highlights new treatment strategies

Cited by 88 publications

References 82 publications

Disrupted Association of Sensory Neurons With Enveloping Satellite Glial Cells in Fragile X Mouse Model

Disrupted Association of Sensory Neurons With Enveloping Satellite Glial Cells in Fragile X Mouse Model

Hyperexcitability and Homeostasis in Fragile X Syndrome

Harnessing the Power of Stem Cell Models to Study Shared Genetic Variants in Congenital Heart Diseases and Neurodevelopmental Disorders

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