Human Models Are Needed for Studying Human Neurodevelopmental Disorders

Zhao, Xinyu; Bhattacharyya, Anita

doi:10.1016/j.ajhg.2018.10.009

Cited by 121 publications

(109 citation statements)

References 374 publications

(431 reference statements)

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“…Thus, human models are critical to identify therapeutic targets likely to impact and benefit human patients. (Zhao and Bhattacharyya, 2018).…”

Section: Discussionmentioning

confidence: 99%

Altered patterning of trisomy 21 interneuron progenitors

Giffin-Rao

Strand

Huang

et al. 2020

Preprint

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Multiple developmental processes go awry in Down syndrome (DS, trisomy 21, Ts21), the most common genetic cause of intellectual disability and a complex multigene disorder. DS individuals have smaller brains with reduced volume of frontal and temporal lobes, including hippocampus. This smaller brain volume corresponds to fewer neurons in the DS cortex measured at pre-and post-natal stages, implicating impaired neurogenesis during development. We employ Ts21 human induced pluripotent stem cells (iPSCs) and isogenic controls to identify disrupted interneuron developmental processes in DS. Interneuron progenitor specification, proliferation and migration is largely controlled by integrating known morphogen gradients, sonic hedgehog (SHH) and Wingless (WNT), and we find that Ts21 progenitors have altered patterning and generate different progenitor populations. Specifically, we find expression of WNT signaling genes is reduced and expression of GLI genes that regulate WNT and SHH signaling in this population is increased in Ts21 interneuron progenitors, suggesting Ts21 progenitors are patterned more ventrally and less caudally. Altered patterning affects lineage decisions and, in fact, fewer caudal interneuron progenitors expressing the transcription factor COUP-TFII differentiate from Ts21 iPSCs. In mouse, COUP-TFII+ progenitors are found in more caudal regions of the neurogenic regions, thus linking the patterning changes to altered generation of interneuron subpopulations. These data identify affected progenitor subpopulations in Ts21 and suggest that abnormal patterning of human Ts21 interneuron progenitors alters the generation of interneurons in DS and contributes to the reduced neurogenesis in DS.

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“…Thus, human models are critical to identify therapeutic targets likely to impact and benefit human patients. (Zhao and Bhattacharyya, 2018).…”

Section: Discussionmentioning

confidence: 99%

Altered patterning of trisomy 21 interneuron progenitors

Giffin-Rao

Strand

Huang

et al. 2020

Preprint

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“…Neuronal development is a complex multistep process in which neurons undergo dramatic morphological changes, including migration, axon outgrowth, dendritogenesis, and synapse formation. Much of the fundamental knowledge about neuronal development is based on experimental studies in non-human model systems, such as Drosophila, C. elegans, mice and rats (Zhao and Bhattacharyya 2018). However, to what extent the knowledge obtained in animal models can be extrapolated to human neuronal development remains largely unclear.…”

Section: Introductionmentioning

confidence: 99%

Quantitative mapping of transcriptome and proteome dynamics during polarization of human iPSC-derived neurons

Lindhout

Kooistra

Portegies

et al. 2020

Preprint

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Early neuronal development is a well-coordinated process in which neuronal stem cells differentiate into polarized neurons. This process has been well studied in classical non-human model systems, but to what extent this is recapitulated in human neurons remains unclear. To study neuronal polarization in human neurons, we cultured human iPSC-derived neurons, characterized early developmental stages, measured electrophysiological responses, and systematically profiled transcriptomic and proteomic dynamics during these steps. We found extensive remodeling of the neuron transcriptome and proteome, with altered mRNA expression of ~1,100 genes and different expression profiles of ~1,500 proteins during neuronal differentiation and polarization. We also identified a distinct stage in axon development marked by an increase in microtubule remodeling and apparent relocation of the axon initial segment from the distal to proximal axon. Our comprehensive characterization and quantitative map of transcriptome and proteome dynamics provides a solid framework for studying polarization in human neurons.(FOM, #16NEPH05, CJW). AUTHOR CONTRIBUTIONSFWL, RK and SP designed the research, conducted experiments, and wrote the article together with LJH. RS conducted and analyzed the mass spectrometry experiments supervised by MA, LJH performed and interpreted the electrophysiology data supervised by CJW, RK and BLS provided and interpreted the RNA sequencing analysis. HDM edited the article. CCH designed the experimental plan, supervised the research and wrote the article.

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“…To date, most research on FMR1 function and consequences of FMR1 loss has relied on animal models, particularly mouse models. However, recent clinical trials developed based on evidence from animal models failed to correct disease-related phenotypes in FXS patients (Bailey et al 2016;Berry-Kravis et al 2016;Zhao and Bhattacharyya 2018). Discrepant impacts of FMR1 deficiency on mouse versus human brains (Kwan et al 2012) and mouse versus human embryonic stem cells (Doers et al 2014;Telias et al 2015;Khalfallah et al 2017) suggest that interspecies differences in brain development and FMR1 function are significant.…”

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confidence: 99%

Identification of FMR1-regulated molecular networks in human neurodevelopment

Shin

Risgaard

et al. 2020

Genome Res.

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RNA-binding proteins (RNA-BPs) play critical roles in development and disease to regulate gene expression. However, genome-wide identification of their targets in primary human cells has been challenging. Here, we applied a modified CLIP-seq strategy to identify genome-wide targets of the FMRP translational regulator 1 (FMR1), a brain-enriched RNA-BP, whose deficiency leads to Fragile X Syndrome (FXS), the most prevalent inherited intellectual disability. We identified FMR1 targets in human dorsal and ventral forebrain neural progenitors and excitatory and inhibitory neurons differentiated from human pluripotent stem cells. In parallel, we measured the transcriptomes of the same four cell types upon FMR1 gene deletion. We discovered that FMR1 preferentially binds long transcripts in human neural cells. FMR1 targets include genes unique to human neural cells and associated with clinical phenotypes of FXS and autism. Integrative network analysis using graph diffusion and multitask clustering of FMR1 CLIP-seq and transcriptional targets reveals critical pathways regulated by FMR1 in human neural development. Our results demonstrate that FMR1 regulates a common set of targets among different neural cell types but also operates in a cell type-specific manner targeting distinct sets of genes in human excitatory and inhibitory neural progenitors and neurons. By defining molecular subnetworks and validating specific high-priority genes, we identify novel components of the FMR1 regulation program. Our results provide new insights into gene regulation by a critical neuronal RNA-BP in human neurodevelopment.

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Human Models Are Needed for Studying Human Neurodevelopmental Disorders

Cited by 121 publications

References 374 publications

Altered patterning of trisomy 21 interneuron progenitors

Altered patterning of trisomy 21 interneuron progenitors

Quantitative mapping of transcriptome and proteome dynamics during polarization of human iPSC-derived neurons

Identification of FMR1-regulated molecular networks in human neurodevelopment

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