Cell stress in cortical organoids impairs molecular subtype specification

Bhaduri, Aparna; Andrews, Madeline G.; Leon, Walter R Mancia; Jung, Diane; Shin, David; Allen, Denise E.; Jung, Dana; Schmunk, Galina; Haeussler, Maximilian; Jahan, Sultana; Pollen, Alex A.; Nowakowski, Tomasz J.; Kriegstein, Arnold R.

doi:10.1038/s41586-020-1962-0

Cited by 408 publications

(507 citation statements)

References 44 publications

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“…3D cultures, also referred to as organoids, which capture more of the architecture (e.g., cortical layering) and cellular environment of in vivo brain development, can be organized by level of directed differentiation going from less directed to highly directed differentiation [32,33,38,[74][75][76]. While all differentiations are initially grown in neural induction media, in the less directed differentiations, the cells are not directed to differentiate into a specific brain region using additional factors [75,[77][78][79][80]. These differentiation methods lead to cultures with a variety of brain regions which can be used to study inter-and intra-regional connections [75,81,82].…”

Section: In Vitro Options For Studying Human Brain Developmentmentioning

confidence: 99%

Human in vitro models for understanding mechanisms of autism spectrum disorder

Gordon

Geschwind

2020

Molecular Autism

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Early brain development is a critical epoch for the development of autism spectrum disorder (ASD). In vivo animal models have, until recently, been the principal tool used to study early brain development and the changes occurring in neurodevelopmental disorders such as ASD. In vitro models of brain development represent a significant advance in the field. Here, we review the main methods available to study human brain development in vitro and the applications of these models for studying ASD and other psychiatric disorders. We discuss the main findings from stem cell models to date focusing on cell cycle and proliferation, cell death, cell differentiation and maturation, and neuronal signaling and synaptic stimuli. To be able to generalize the results from these studies, we propose a framework of experimental design and power considerations for using in vitro models to study ASD. These include both technical issues such as reproducibility and power analysis and conceptual issues such as the brain region and cell types being modeled.Early development as a critical period for ASD susceptibility

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Section: In Vitro Options For Studying Human Brain Developmentmentioning

confidence: 99%

Human in vitro models for understanding mechanisms of autism spectrum disorder

Gordon

Geschwind

2020

Molecular Autism

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“…To confirm the identity of our cell types, we integrated our organoid data with recently published single-cell data from fetal brains of various developmental ages 10 . The fetal samples have been sequenced on the same platform (10X Chromium) and were obtained from https://cells.ucsc.edu.…”

Section: Methodsmentioning

confidence: 99%

“…2C). To analyze whether this neural progenitor is also found in vivo we compared our data to a published scRNA-Seq dataset of the developing human fetal brain 30 . After integrating these data with our dataset, unsupervised clustering identified the same cluster in fetal brains (cluster 18 Ext.…”

Section: Single Cell Analysis Of Tsc2+/− Organoids Reveals a Caudal Pmentioning

confidence: 99%

Cerebral organoid model reveals excessive proliferation of human caudal late interneuron progenitors in Tuberous Sclerosis Complex

Eichmüller

Corsini

Vértesy

et al. 2020

Preprint

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29Although the intricate and prolonged development of the human brain critically 30 distinguishes it from other mammals 1 , our current understanding of 31 neurodevelopmental diseases is largely based on work using animal models. Recent 32 studies revealed that neural progenitors in the human brain are profoundly different 33 from those found in rodent animal models [2][3][4][5] . Moreover, post-mortem studies 34 revealed extensive migration of interneurons into the late-gestational and post-natal 35 human prefrontal cortex that does not occur in rodents 6 . Here, we use cerebral 36 organoids to show that overproduction of mid-gestational human interneurons 37 causes Tuberous Sclerosis Complex (TSC), a severe neuro-developmental disorder 38 associated with mutations in TSC1 and TSC2. We identify a previously 39 uncharacterized population of caudal late interneuron progenitors, the CLIP-cells. In 40 organoids derived from patients carrying heterozygous TSC2 mutations, 41 dysregulation of mTOR signaling leads to CLIP-cell over-proliferation and formation 42 of cortical tubers and subependymal tumors. Surprisingly, second-hit events 43 resulting from copy-neutral loss-of-heterozygosity (cnLOH) are not causative for but 44 occur during the progression of tumor lesions. Instead, EGFR signaling is required 45 for tumor proliferation, opening up a promising approach to treat TSC lesions. Our 46 study demonstrates that the analysis of developmental disorders in organoid models 47 can lead to fundamental insights into human brain development and neuropsychiatric 48 disorders. 49Tuberous sclerosis complex (TSC) is a rare autosomal dominant disorder 50 characterized by pathological malformations in multiple organs 7 . Among those, brain 51 defects leading to severe neuropsychiatric symptoms like autism spectrum disorder 52 (ASD), intractable seizures and intellectual disability (ID) are most debilitating and 53 seen in the majority of patients 8 . Most patients have cortical tubers 9 , focal dysplastic 54 regions in the cortex that are diagnosed by MRI and consist of dysmorphic neurons 55 and giant cells. In addition, 80% of the patients display subependymal nodules 56 (SEN) that form along the lateral ventricle and can develop into subependymal giant 57 cell astrocytomas (SEGAs) in 10-15% of the patients 7,10 . It was thought that TSC 58 pathogenesis is initiated by constitutive mTOR activity resulting from inactivation of 59 the second allele 11 along the lines of the classic Knudson two-hit hypothesis of 60 tumorigenesis 12 . This is supported by existing mouse models and a spheroid model 61 for TSC, as characteristic brain alterations are observed exclusively in Tsc1 or Tsc2 62 homozygous mutant mice and spheroids [13][14][15][16][17][18] . Genetic analysis in patients, however, 63 revealed that loss of the second allele is frequent in SEN/SEGA, but rare in cortical 64 tubers 19-22 , conflicting with the two-hit hypothesis. In addition, the cellular origins of 65 cortical tubers and SEN/SEGAs remain unclear. Interesting...

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“…While organoids perhaps bring us closer to human biology, this model system has its own limitations. Most notably, recent work has shown that these artificial systems ectopically activate cellular stress pathways, which can impact cell type specification 58…”

Section: Generating Mouse and Organoid Models Of Diseasementioning

confidence: 99%

Establishing a transcriptome-based drug discovery paradigm for neurodevelopmental disorders

Dhindsa

Zoghbi

Krizay

et al. 2020

Preprint

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Advances in genetic discoveries have created substantial opportunities for precision medicine in neurodevelopmental disorders. Many of the genes implicated in these diseases encode proteins that regulate gene expression, such as chromatin associated proteins, transcription factors, and RNA-binding proteins. The identification of targeted therapeutics for individuals carrying mutations in these genes remains a challenge, as the encoded proteins can theoretically regulate thousands of downstream targets in a considerable number of cell types. Here, we propose the application of a drug discovery approach called "transcriptome reversal" for these disorders. This approach, originally developed for cancer, attempts to identify compounds that reverse gene-expression signatures associated with disease states.

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Cell stress in cortical organoids impairs molecular subtype specification

Cited by 408 publications

References 44 publications

Human in vitro models for understanding mechanisms of autism spectrum disorder

Human in vitro models for understanding mechanisms of autism spectrum disorder

Cerebral organoid model reveals excessive proliferation of human caudal late interneuron progenitors in Tuberous Sclerosis Complex

Establishing a transcriptome-based drug discovery paradigm for neurodevelopmental disorders

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