Application of Human Brain Organoids—Opportunities and Challenges in Modeling Human Brain Development and Neurodevelopmental Diseases DOI Open Access
S.Y. Kim, Mi‐Yoon Chang

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(15), P. 12528 - 12528

Published: Aug. 7, 2023

Brain organoids are three-dimensional (3D) structures derived from human pluripotent stem cells (hPSCs) that reflect early brain organization. These contain different cell types, including neurons and glia, similar to those found in the brain. Human provide unique opportunities model features of development not well-reflected animal models. Compared with traditional cultures models, offer a more accurate representation function, rendering them suitable models for neurodevelopmental diseases. In particular, patients’ have enabled researchers study diseases at stages gain better understanding disease mechanisms. Multi-brain regional assembloids allow investigation interactions between distinct regions while achieving higher level consistency molecular functional characterization. Although possess promising features, their usefulness is limited by several unresolved constraints, cellular stress, hypoxia, necrosis, lack high-fidelity maturation, circuit formation. this review, we discuss studies overcome natural limitations organoids, emphasizing importance combinations all neural such as glia (astrocyte, oligodendrocytes, microglia) vascular cells. Additionally, considering similarity developing brain, regionally patterned organoid-derived (NSCs) could serve scalable source replacement therapy. We highlight potential application therapy within field.

Language: Английский

High-throughput functional analysis of autism genes in zebrafish identifies convergence in dopaminergic and neuroimmune pathways DOI Creative Commons
Hellen Weinschutz Mendes,

Uma Neelakantan,

Yunqing Liu

et al.

Cell Reports, Journal Year: 2023, Volume and Issue: 42(3), P. 112243 - 112243

Published: March 1, 2023

Advancing from gene discovery in autism spectrum disorders (ASDs) to the identification of biologically relevant mechanisms remains a central challenge. Here, we perform parallel vivo functional analysis 10 ASD genes at behavioral, structural, and circuit levels zebrafish mutants, revealing both unique overlapping effects loss function. Whole-brain mapping identifies forebrain cerebellum as most significant contributors brain size differences, while regions involved sensory-motor control, particularly dopaminergic regions, are associated with altered baseline activity. Finally, show global increase microglia resulting function select implicating neuroimmune dysfunction key pathway biology.

Language: Английский

Citations

44
Brain Chimeroids reveal individual susceptibility to neurotoxic triggers DOI
Noelia Antón-Bolaños, Irene Faravelli, Tyler Faits

et al.

Nature, Journal Year: 2024, Volume and Issue: 631(8019), P. 142 - 149

Published: June 26, 2024

Language: Английский

Citations

35
An integrated transcriptomic cell atlas of human neural organoids DOI Creative Commons
Zhisong He, Leander Dony, Jonas Simon Fleck

et al.

Nature, Journal Year: 2024, Volume and Issue: 635(8039), P. 690 - 698

Published: Nov. 20, 2024

Human neural organoids, generated from pluripotent stem cells in vitro, are useful tools to study human brain development, evolution and disease. However, it is unclear which parts of the covered by existing protocols, has been difficult quantitatively assess organoid variation fidelity. Here we integrate 36 single-cell transcriptomic datasets spanning 26 protocols into one integrated cell atlas totalling more than 1.7 million cells1–26. Mapping developing references27–30 shows primary types states that have estimates similarity between counterparts across protocols. We provide a programmatic interface browse query new datasets, showcase power annotate evaluate Finally, show can be used as diverse control cohort compare models disease, identifying genes pathways may underlie pathological mechanisms with models. The will fidelity, characterize perturbed diseased facilitate protocol development. A integrating counterparts, showing potential fidelity

Language: Английский

Citations

23
Autism Spectrum Disorder: Brain Areas Involved, Neurobiological Mechanisms, Diagnoses and Therapies DOI Open Access
Jacopo Lamanna, Jacopo Meldolesi

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(4), P. 2423 - 2423

Published: Feb. 19, 2024

Autism spectrum disorder (ASD), affecting over 2% of the pre-school children population, includes an important fraction conditions accounting for heterogeneity autism. The disease was discovered 75 years ago, and present review, based on critical evaluations recognized ASD studies from beginning 1990, has been further developed by comparative analyses research clinical reports, which have grown progressively in recent up to late 2023. tools necessary identification its related pathologies are genetic epigenetic mutations affected specific interaction with transcription factors chromatin remodeling processes occurring within complexes brain neurons. Most often, ensuing effects induce inhibition/excitation synaptic structures sustained primarily, at dendritic fibers, alterations flat spine response sites. These relevant because synapses, established interactions neurons glial cells, operate as early key targets ASD. pathology is often suspected parents communities then confirmed experiences. final diagnoses mature patients completed combination neuropsychological (cognitive) tests electro-/magneto-encephalography specialized centers. comorbidities, induced such anxieties, depressions, hyperactivities, sleep defects, interact reinforce other diseases, especially schizophrenia. Advanced therapies, prescribed adult control symptoms disease, well-known drugs classical neurologic psychiatric practice. Overall, this review reports discusses advanced knowledge about biological medical properties

Language: Английский

Citations

17
Autism spectrum disorder: pathogenesis, biomarker, and intervention therapy DOI Creative Commons
Hongbin Zhuang, Zhiyuan Liang,

Guanwei Ma

et al.

MedComm, Journal Year: 2024, Volume and Issue: 5(3)

Published: March 1, 2024

Abstract Autism spectrum disorder (ASD) has become a common neurodevelopmental disorder. The heterogeneity of ASD poses great challenges for its research and clinical translation. On the basis reviewing ASD, this review systematically summarized current status progress pathogenesis, diagnostic markers, interventions ASD. We provided an overview molecular mechanisms identified by multi‐omics studies convergent mechanism in different genetic backgrounds. comorbidities, associated with important physiological metabolic abnormalities (i.e., inflammation, immunity, oxidative stress, mitochondrial dysfunction), gut microbial were reviewed. non‐targeted omics targeting markers also Moreover, we methods behavioral educational interventions, intervention related to technological devices, on medical potential drug targets. This highlighted application high‐throughput emphasized importance seeking homogeneity from exploring convergence disease mechanisms, biomarkers, approaches, proposes that taking into account individuality commonality may be key achieve accurate diagnosis treatment

Language: Английский

Citations

16
Autism-Associated Genes and Neighboring lncRNAs Converge on Key Gene Regulatory Networks DOI Creative Commons
Rebecca Andersen, Maya Talukdar, T. Sakamoto

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 22, 2025

The diversity of genes implicated in autism spectrum disorder (ASD) creates challenges for identifying core pathophysiological mechanisms. Aggregation seven different classes genetic variants ASD, a database we call Consensus-ASD , reveals shared features across distinct types ASD variants. Functional interrogation 19 and 9 neighboring long non-coding RNAs (lncRNAs) using CRISPR-Cas13 strikingly revealed differential gene expression profiles that were significantly enriched other genes. Furthermore, construction regulatory network (GRN) enabled the identification central regulators exhibit convergently altered activity upon disruption. Thus, this study how perturbing ASD-associated can lead to shared, broad dysregulation GRNs with critical relevance ASD. This provides crucial framework understanding diverse genes, including lncRNAs, play convergent roles key neurodevelopmental processes ultimately contribute

Language: Английский

Citations

2
A subpopulation of cortical neurons altered by mutations in the autism risk gene DDX3X DOI Creative Commons
Michael Flores, Marta García-Forn,

Alexa von Mueffling

et al.

Biology Open, Journal Year: 2025, Volume and Issue: 14(1)

Published: Jan. 15, 2025

ABSTRACT Cell fate decisions during cortical development sculpt the identity of long-range connections that subserve complex behaviors. These are largely dictated by mutually exclusive transcription factors, including CTIP2/Bcl11b for subcerebral projection neurons and BRN1/Pou3f3 intra-telencephalic neurons. We have recently reported balance CTIP2-expressing is altered in a mouse model DDX3X syndrome, female-biased neurodevelopmental disorder associated with intellectual disability, autism spectrum disorder, significant motor challenges. Here, we studied developmental dynamics subpopulation co-expressing CTIP2 BRN1. found CTIP2+BRN1+ born early phases neurogenesis like other CTIP2+ neurons, peak expression perinatal life, persist adult brains. also excessive number prenatal mature areas Ddx3x mutant mice, translating into laminar distribution extending axons to brainstem. findings underscore critical role molecular specification health disease.

Language: Английский

Citations

2
Epidemiology of autism spectrum disorders: Global burden of disease 2019 and bibliometric analysis of risk factors DOI Creative Commons
Yang-An Li, Zejian Chen, Xiaodan Li

et al.

Frontiers in Pediatrics, Journal Year: 2022, Volume and Issue: 10

Published: Dec. 5, 2022

To explore the geographical pattern and temporal trend of autism spectrum disorders (ASD) epidemiology from 1990 to 2019, perform a bibliometric analysis risk factors for ASD.In this study, ASD was estimated with prevalence, incidence, disability-adjusted life-years (DALYs) 204 countries territories by sex, location, sociodemographic index (SDI). Age-standardized rate (ASR) annual percentage change (EAPC) were used quantify trends. Besides, study performed since 1990. Publications published downloaded Web Science Core Collection database, analyzed using CiteSpace.Globally, there 28.3 million prevalent cases (ASR, 369.4 per 100,000 populations), 603,790 incident 9.3 populations) 4.3 DALYs 56.3 in 2019. Increases noted (39.3%), incidence (0.1%), (38.7%) rates EAPC showed stable worldwide over time. A total 3,991 articles retrieved Science, which 3,590 obtained after removing duplicate literatures. "Rehabilitation", "Genetics & Heredity", "Nanoscience Nanotechnology", "Biochemistry Molecular biology", "Psychology", "Neurosciences", "Environmental Sciences" hotspots frontier disciplines factors.Disease burden remain global public health challenge according GBD epidemiological estimates analysis. The findings help policy makers formulate policies concerning prevention targeted factors, early diagnosis life-long healthcare service ASD. Increasing knowledge awareness is also warranted address problem.

Language: Английский

Citations

44
Scalable genetic screening for regulatory circuits using compressed Perturb-seq DOI Creative Commons
Douglas Yao, Loïc Binan, Jon Bezney

et al.

Nature Biotechnology, Journal Year: 2023, Volume and Issue: 42(8), P. 1282 - 1295

Published: Oct. 23, 2023

Abstract Pooled CRISPR screens with single-cell RNA sequencing readout (Perturb-seq) have emerged as a key technique in functional genomics, but they are limited scale by cost and combinatorial complexity. In this study, we modified the design of Perturb-seq incorporating algorithms applied to random, low-dimensional observations. Compressed measures multiple random perturbations per cell or cells droplet computationally decompresses these measurements leveraging sparse structure regulatory circuits. Applied 598 genes immune response bacterial lipopolysaccharide, compressed achieves same accuracy conventional an order magnitude reduction greater power learn genetic interactions. We identified known novel regulators responses uncovered evolutionarily constrained downstream targets enriched for disease heritability, including many missed existing genome-wide association studies. Our framework enables new scales interrogation foundational method genomics.

Language: Английский

Citations

38
Non-synaptic function of the autism spectrum disorder-associated gene SYNGAP1 in cortical neurogenesis DOI
Marcella Birtele,

Ashley Del Dosso,

Tiantian Xu

et al.

Nature Neuroscience, Journal Year: 2023, Volume and Issue: 26(12), P. 2090 - 2103

Published: Nov. 9, 2023

Language: Английский

Citations

38