scholarly journals Antiviral signalling in human IPSC-derived neurons recapitulates neurodevelopmental disorder phenotypes

2019 ◽  
Author(s):  
Katherine Warre-Cornish ◽  
Leo Perfect ◽  
Roland Nagy ◽  
Matthew J. Reid ◽  
Annett Mueller ◽  
...  
Keyword(s):  
Neurite Outgrowth ◽  
Viral Entry ◽  
Neurodevelopmental Disorders ◽  
Neurodevelopmental Disorder ◽  
Risk Genes ◽  
Maternal Immune Activation ◽  
Pml Bodies ◽  
Induced Pluripotent ◽  
Cellular Phenotypes ◽  
Human Ipsc

AbstractMaternal immune activation increases the risk of neurodevelopmental disorders. Elevated cytokines, such as interferon-gamma (IFNγ), in offspring’s brains play a central role. IFNγ activates an antiviral cellular state, limiting viral entry and replication. In addition, IFNγ has been implicated in brain development. Here, we hypothesise that IFNγ-induced antiviral signalling contributes to molecular and cellular phenotypes associated with neurodevelopmental disorders. We find that transient IFNγ treatment of neural progenitors derived from human induced pluripotent stem cells (hIPSCs) persistently increases neurite outgrowth, phenocopying hIPSC-neurons from autistic individuals. IFNγ upregulates antiviral PML bodies and MHC class I (MHCI) genes, which persists through neuronal differentiation. Critically, IFNγ-induced neurite outgrowth requires both PML and MHCI. We also find that IFNγ disproportionately alters expression of autism and schizophrenia risk genes, suggesting convergence between these genetic and environmental risk factors. Together, these data indicate that IFNγ-induced antiviral signalling may contribute to neurodevelopmental disorder aetiology.

scholarly journals Interferon-γ signaling in human iPSC–derived neurons recapitulates neurodevelopmental disorder phenotypes

2020 ◽  
Vol 6 (34) ◽  
pp. eaay9506
Author(s):  
Katherine Warre-Cornish ◽  
Leo Perfect ◽  
Roland Nagy ◽  
Rodrigo R. R. Duarte ◽  
Matthew J. Reid ◽  
...  
Keyword(s):  
Neurite Outgrowth ◽  
Viral Entry ◽  
Neurodevelopmental Disorders ◽  
Neurodevelopmental Disorder ◽  
Interferon Γ ◽  
Nuclear Bodies ◽  
Sequencing Analysis ◽  
Pml Nuclear Bodies ◽  
Ifn Γ ◽  
Cellular Phenotypes

Maternal immune activation increases the risk of neurodevelopmental disorders. Elevated cytokines, such as interferon-γ (IFN-γ), in offspring’s brains play a central role. IFN-γ activates an antiviral cellular state, limiting viral entry and replication. Moreover, IFN-γ is implicated in brain development. We tested the hypothesis that IFN-γ signaling contributes to molecular and cellular phenotypes associated with neurodevelopmental disorders. Transient IFN-γ treatment of neural progenitors derived from human induced pluripotent stem cells increased neurite outgrowth. RNA sequencing analysis revealed that major histocompatibility complex class I (MHCI) genes were persistently up-regulated through neuronal differentiation—an effect that was mediated by IFN-γ-induced promyelocytic leukemia protein (PML) nuclear bodies. Critically, IFN-γ-induced neurite outgrowth required both PML and MHCI. We also found evidence that IFN-γ disproportionately altered the expression of genes associated with schizophrenia and autism, suggesting convergence between genetic and environmental risk factors. Together, these data implicate IFN-γ signaling in neurodevelopmental disorder etiology.

scholarly journals Brain-Specific Deletion of GIT1 Impairs Cognition and Alters Phosphorylation of Synaptic Protein Networks Implicated in Schizophrenia Susceptibility

2018 ◽  
Author(s):  
Daniel M. Fass ◽  
Michael C. Lewis ◽  
Rushdy Ahmad ◽  
Matthew J. Szucs ◽  
Qiangge Zhang ◽  
...  
Keyword(s):  
Cognitive Deficits ◽  
Neurodevelopmental Disorders ◽  
Rare Variants ◽  
Neurodevelopmental Disorder ◽  
Copy Number Variants ◽  
Synaptic Proteins ◽  
Interacting Protein ◽  
Risk Genes ◽  
Multiple Loci ◽  
Coding Variants

AbstractDespite tremendous effort, the molecular and cellular basis of cognitive deficits in schizophrenia remain poorly understood. Recent progress in elucidating the genetic architecture of schizophrenia has highlighted the association of multiple loci and rare variants that may impact susceptibility. One key example, given their potential etiopathogenic and therapeutic relevance, is a set of genes that encode proteins that regulate excitatory glutamatergic synapses in brain. A critical next step is to delineate specifically how such genetic variation impacts synaptic plasticity and to determine if and how the encoded proteins interact biochemically with one another to control cognitive function in a convergent manner. Towards this goal, here we study the roles of GPCR-kinase interacting protein 1 (GIT1), a synaptic scaffolding and signaling protein with damaging coding variants found in schizophrenia patients, as well as copy number variants found in patients with neurodevelopmental disorders. We generated conditional neural-selective GIT1 knockout mice and find that these mice have deficits in fear conditioning learning and spatial memory. Using global quantitative phospho-proteomics, we revealed that GIT1 deletion in brain perturbs specific networks of GIT1-interacting synaptic proteins. Importantly, several schizophrenia and neurodevelopmental disorder risk genes are present within these networks. We propose that GIT1 regulates the phosphorylation of a network of synaptic proteins and other critical regulators of neuroplasticity, and that perturbation of these networks may contribute to cognitive deficits observed in schizophrenia and neurodevelopmental disorders.

scholarly journals Genetic subtypes, allelic effects, and convergent neurodevelopmental mechanisms

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Maitreya Das ◽  
Santhosh Girirajan
Keyword(s):  
Neurodevelopmental Disorders ◽  
High Throughput Sequencing ◽  
Complex Disease ◽  
Molecular Subtype ◽  
Neurodevelopmental Disorder ◽  
Disease Etiology ◽  
Risk Genes ◽  
Genetic Subtypes ◽  
Risk Variants ◽  
Functional Consequences

AbstractHigh-throughput sequencing of large affected cohorts have helped uncover a plethora of risk genes for complex neurodevelopmental disorders. However, untangling complex disease etiology also involves understanding the functional consequences of these mutations in order to connect risk variants to resulting phenotypes. Here, we highlight the efforts of Mannucci and colleagues to define a novel molecular subtype of neurodevelopmental disorder associated with mutations in DHX30 and characterize location-specific mutational effects in cell culture and zebrafish models.

scholarly journals OLIG2 Drives Abnormal Neurodevelopmental Phenotypes in Human iPSC-Based Organoid and Chimeric Mouse Models of Down Syndrome

2018 ◽  
Author(s):  
Ranjie Xu ◽  
Andrew T Brawner ◽  
Shenglan Li ◽  
JingJing Liu ◽  
Hyosung Kim ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Early Stage ◽  
Neurodevelopmental Disorder ◽  
Neural Progenitors ◽  
Chimeric Mouse ◽  
Chimeric Mice ◽  
Neurodevelopmental Abnormalities ◽  
Induced Pluripotent ◽  
Human Ipsc ◽  
Cognitive Defects

SUMMARYDown syndrome (DS) is a common neurodevelopmental disorder, and cognitive defects in DS patients may arise form imbalances in excitatory and inhibitory neurotransmission. Understanding the mechanisms underlying such imbalances may provide opportunities for therapeutic intervention. Here, we show that human induced pluripotent stem cells (hiPSCs) derived from DS patients overproduce OLIG2+ ventral forebrain neural progenitors. As a result, DS hiPSC-derived cerebral organoids excessively produce specific subclasses of GABAergic interneurons and cause impaired recognition memory in neuronal chimeric mice. Increased OLIG2 expression in DS cells directly upregulates interneuron lineage-determining transcription factors. shRNA-mediated knockdown of OLIG2 largely reverses abnormal gene expression in early-stage DS neural progenitors, reduces interneuron production in DS organoids and chimeric mouse brains, and improves behavioral deficits in DS chimeric mice. Thus, altered OLIG2 expression may underlie neurodevelopmental abnormalities and cognitive defects in DS patients.

scholarly journals Interferon-ɣ Exposure of Human iPSC-derived Neurons Alters Major Histocompatibility Complex I and Synapsin I Protein Expression

2021 ◽  
Author(s):  
Adam Pavelinek ◽  
Rugile Matuleviciute ◽  
Laura Sichlinger ◽  
Lucia Dutan Polit ◽  
Nikos Armeniakos ◽  
...  
Keyword(s):  
Immune Activation ◽  
Neurodevelopmental Disorders ◽  
Synapse Formation ◽  
Neurodevelopmental Disorder ◽  
Synaptic Proteins ◽  
Synapsin I ◽  
Mrna Levels ◽  
Maternal Immune Activation ◽  
Increased Risk

Human epidemiological data links maternal immune activation during gestation with increased risk for neurodevelopmental disorders including schizophrenia. Animal models of maternal immune activation (MIA) provide causal evidence for this association and strongly suggest that inflammatory cytokines act is a critical link between maternal infection and aberrant offspring brain and behavior development. This includes evidence for reduced synapse formation, consistent with post-mortem and in vivo evidence of reduced synaptic density in schizophrenia. However, to what extent specific cytokines are necessary and sufficient for these effects remains unclear. Using a human cellular model, we recently demonstrated that acute exposure to interferon-ɣ (IFNɣ) recapitulates molecular and cellular phenotypes associated with neurodevelopmental disorders. Here, we extend this work to test whether IFNɣ affects synapse formation in an induced neuron model that generates forebrain glutamatergic neurons. Using immunocytochemistry and quantitative PCR, we demonstrate that acute IFNɣ exposure results in significantly increased MHCI expression at the mRNA and protein level. Furthermore, acute IFNɣ exposure decreases synapsin I protein in neurons but does not affect synaptic gene mRNA levels. Interestingly, complement component 4A (C4A) mRNA is also significantly increased following acute IFNɣ exposure. This study builds on our previous work by showing that IFNɣ-mediated disruption of relevant synaptic proteins can occur at early stages of synapse formation, potentially contributing to neurodevelopmental disorder phenotypes such as schizophrenia.

scholarly journals CNTN5-/+or EHMT2-/+human iPSC-derived neurons from individuals with autism develop hyperactive neuronal networks

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Eric Deneault ◽  
Muhammad Faheem ◽  
Sean H White ◽  
Deivid C Rodrigues ◽  
Song Sun ◽  
...  
Keyword(s):  
De Novo ◽  
Electrode Array ◽  
Induced Pluripotent Stem Cell ◽  
Autism Spectrum ◽  
Editorial Note ◽  
Risk Genes ◽  
Risk Variants ◽  
Induced Pluripotent ◽  
Relationship Of ◽  
Human Ipsc

Induced pluripotent stem cell (iPSC)-derived neurons are increasingly used to model Autism Spectrum Disorder (ASD), which is clinically and genetically heterogeneous. To study the complex relationship of penetrant and weaker polygenic risk variants to ASD, ‘isogenic’ iPSC-derived neurons are critical. We developed a set of procedures to control for heterogeneity in reprogramming and differentiation, and generated 53 different iPSC-derived glutamatergic neuronal lines from 25 participants from 12 unrelated families with ASD. Heterozygous de novo and rare-inherited presumed-damaging variants were characterized in ASD risk genes/loci. Combinations of putative etiologic variants (GLI3/KIF21A or EHMT2/UBE2I) in separate families were modeled. We used a multi-electrode array, with patch-clamp recordings, to determine a reproducible synaptic phenotype in 25% of the individuals with ASD (other relevant data on the remaining lines was collected). Our most compelling new results revealed a consistent spontaneous network hyperactivity in neurons deficient for CNTN5 or EHMT2. The biobank of iPSC-derived neurons and accompanying genomic data are available to accelerate ASD research.Editorial note: This article has been through an editorial process in which authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (<xref ref-type="decision-letter" rid="SA1">see decision letter</xref>).

scholarly journals An Efficient Method for the Differentiation of Human iPSC-Derived Endoderm toward Enterocytes and Hepatocytes

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 812
Author(s):  
Shimeng Qiu ◽  
Yaling Li ◽  
Yuki Imakura ◽  
Shinji Mima ◽  
Tadahiro Hashita ◽  
...  
Keyword(s):  
Small Intestine ◽  
Activin A ◽  
Double Positive ◽  
Differentiation Method ◽  
Drug Metabolizing Enzyme ◽  
Human Ipscs ◽  
Novel Method ◽  
Induced Pluripotent ◽  
Metabolizing Enzyme ◽  
Human Ipsc

The endoderm, differentiated from human induced pluripotent stem cells (iPSCs), can differentiate into the small intestine and liver, which are vital for drug absorption and metabolism. The development of human iPSC-derived enterocytes (HiEnts) and hepatocytes (HiHeps) has been reported. However, pharmacokinetic function-deficiency of these cells remains to be elucidated. Here, we aimed to develop an efficient differentiation method to induce endoderm formation from human iPSCs. Cells treated with activin A for 168 h expressed higher levels of endodermal genes than those treated for 72 h. Using activin A (days 0–7), CHIR99021 and PI−103 (days 0–2), and FGF2 (days 3–7), the hiPSC-derived endoderm (HiEnd) showed 97.97% CD−117 and CD−184 double-positive cells. Moreover, HiEnts derived from the human iPSC line Windy had similar or higher expression of small intestine-specific genes than adult human small intestine. Activities of the drug transporter P-glycoprotein and drug-metabolizing enzyme cytochrome P450 (CYP) 3A4/5 were confirmed. Additionally, Windy-derived HiHeps expressed higher levels of hepatocyte- and pharmacokinetics-related genes and proteins and showed higher CYP3A4/5 activity than those derived through the conventional differentiation method. Thus, using this novel method, the differentiated HiEnts and HiHeps with pharmacokinetic functions could be used for drug development.

scholarly journals LSD1 enzyme inhibitor TAK-418 unlocks aberrant epigenetic machinery and improves autism symptoms in neurodevelopmental disorder models

2021 ◽  
Vol 7 (11) ◽  
pp. eaba1187
Author(s):  
Rina Baba ◽  
Satoru Matsuda ◽  
Yuuichi Arakawa ◽  
Ryuji Yamada ◽  
Noriko Suzuki ◽  
...  
Keyword(s):  
Gene Expression ◽  
Enzyme Activity ◽  
Neurodevelopmental Disorders ◽  
Neurodevelopmental Disorder ◽  
Specific Inhibitor ◽  
Autism Spectrum ◽  
Poly I:C ◽  
Control Of Gene Expression ◽  
Epigenetic Machinery ◽  
The Brain

Persistent epigenetic dysregulation may underlie the pathophysiology of neurodevelopmental disorders, such as autism spectrum disorder (ASD). Here, we show that the inhibition of lysine-specific demethylase 1 (LSD1) enzyme activity normalizes aberrant epigenetic control of gene expression in neurodevelopmental disorders. Maternal exposure to valproate or poly I:C caused sustained dysregulation of gene expression in the brain and ASD-like social and cognitive deficits after birth in rodents. Unexpectedly, a specific inhibitor of LSD1 enzyme activity, 5-((1R,2R)-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)thiophene-3-carboxamide hydrochloride (TAK-418), almost completely normalized the dysregulated gene expression in the brain and ameliorated some ASD-like behaviors in these models. The genes modulated by TAK-418 were almost completely different across the models and their ages. These results suggest that LSD1 enzyme activity may stabilize the aberrant epigenetic machinery in neurodevelopmental disorders, and the inhibition of LSD1 enzyme activity may be the master key to recover gene expression homeostasis. TAK-418 may benefit patients with neurodevelopmental disorders.

scholarly journals Molecular characterisation of rare loss-of-function NPAS3 and NPAS4 variants identified in individuals with neurodevelopmental disorders

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Joseph J. Rossi ◽  
Jill A. Rosenfeld ◽  
Katie M. Chan ◽  
Haley Streff ◽  
Victoria Nankivell ◽  
...  
Keyword(s):  
Neurodevelopmental Disorders ◽  
Protein Function ◽  
Transcriptional Activity ◽  
Neurodevelopmental Disorder ◽  
Complete Loss ◽  
Loss Of Function ◽  
Targeted Disruption ◽  
Clinical Exome Sequencing ◽  
Partner Protein ◽  
The Brain

AbstractAberrations in the excitatory/inhibitory balance within the brain have been associated with both intellectual disability (ID) and schizophrenia (SZ). The bHLH-PAS transcription factors NPAS3 and NPAS4 have been implicated in controlling the excitatory/inhibitory balance, and targeted disruption of either gene in mice results in a phenotype resembling ID and SZ. However, there are few human variants in NPAS3 and none in NPAS4 that have been associated with schizophrenia or neurodevelopmental disorders. From a clinical exome sequencing database we identified three NPAS3 variants and four NPAS4 variants that could potentially disrupt protein function in individuals with either developmental delay or ID. The transcriptional activity of the variants when partnered with either ARNT or ARNT2 was assessed by reporter gene activity and it was found that variants which truncated the NPAS3/4 protein resulted in a complete loss of transcriptional activity. The ability of loss-of-function variants to heterodimerise with neuronally enriched partner protein ARNT2 was then determined by co-immunoprecipitation experiments. It was determined that the mechanism for the observed loss of function was the inability of the truncated NPAS3/4 protein to heterodimerise with ARNT2. This further establishes NPAS3 and NPAS4 as candidate neurodevelopmental disorder genes.

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