High-throughput functional analysis of autism genes in zebrafish identifies convergence in dopaminergic and neuroimmune pathways

Mendes, Hellen Weinschutz; Neelakantan, Uma; Liu, Yunqing; Fitzpatrick, Sarah E.; Chen, Tianying; Wu, Weimiao; Pruitt, April; Jin, David; Jamadagni, Priyanka; Carlson, Marina; Lacadie, Cheryl; Enriquez, Kristen; Li, Ningshan; Zhao, Dejian; Ijaz, Sundas; Sakai, Catalina; Szi, Christina; Rooney, Brendan; Ghosh, Marcus; Nwabudike, Ijeoma; Gorodezky, Andrea; Chowdhury, Sumedha; Zaheer, Meeraal; McLaughlin, Sarah; Fernandez, Joseph; Wu, Jia Qian; Eilbott, Jeffrey; Wyk, Brent Vander; Rihel, Jason; Papademetris, Xenophon; Wang, Zuoheng; Hoffman, Ellen J.

doi:10.1016/j.celrep.2023.112243

Cited by 22 publications

(22 citation statements)

References 99 publications

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“…Overall, we identify a clear point of convergence around neurogenesis, expanding the generalizability of a large body of work 8,[12][13][14][15][16][17][18][19][20][21][22][23][24][26][27][28][29][30][32][33][34] . Specifically, we observe that disruption of hcASD genes in general biases cells towards the Cycling 2 cluster-a population of cells that may represent a transitional cell state, bridging Cycling 1 and Intermediate cells.…”

Section: Discussionmentioning

confidence: 91%

“…Excitingly however, the advent of high throughput, CRISPR-based approaches enables highly parallelized functional studies aiming to link disruptions of these genes to specific molecular processes and phenotypes shared across a large number of hcASD genes, thereby pinpointing convergent points of biology relevant to at least a subset of patients with ASD. There have been three parallelized in vivo screens of a smaller number of hcASD genes (10-35 genes) conducted to date 20,24,26 . All three implicated excitatory neurogenesis, but the specific molecular processes underlying this convergent phenotype were not elaborated.…”

Section: Discussionmentioning

confidence: 99%

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Autism genes converge on microtubule biology and RNA-binding proteins during excitatory neurogenesis

Sun,

Teyssier,

Wang

et al. 2023

Preprint

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SummaryRecent studies have identified over one hundred high-confidence (hc) autism spectrum disorder (ASD) genes. Systems biological and functional analyses on smaller subsets of these genes have consistently implicated excitatory neurogenesis. However, the extent to which the broader set of hcASD genes are involved in this process has not been explored systematically nor have the biological pathways underlying this convergence been identified. Here, we leveraged CROP-Seq to repress 87 hcASD genes in a humanin vitromodel of cortical neurogenesis. We identified 17 hcASD genes whose repression significantly alters developmental trajectory and results in a common cellular state characterized by disruptions in proliferation, differentiation, cell cycle, microtubule biology, and RNA-binding proteins (RBPs). We also characterized over 3,000 differentially expressed genes, 286 of which had expression profiles correlated with changes in developmental trajectory. Overall, we uncovered transcriptional disruptions downstream of hcASD gene perturbations, correlated these disruptions with distinct differentiation phenotypes, and reinforced neurogenesis, microtubule biology, and RBPs as convergent points of disruption in ASD.

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Autism genes converge on microtubule biology and RNA-binding proteins during excitatory neurogenesis

Sun,

Teyssier,

Wang

et al. 2023

Preprint

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“…Studies in people with genetic forms of autism and in animal models show that, despite some shared aspects of etiology, including changes to neuro-and gliogenesis and altered excitatory/inhibitory balance (Hoffman et al, 2016;Willsey et al, 2021), detailed changes in neuroanatomy, behavioral profiles, and associated symptoms exhibit substantial differences by genotype supporting the existence of autism subtypes (Ellegood et al, 2015;Thyme et al, 2019;Zerbi et al, 2021;Weinschutz Mendes et al, 2023). In the case of SYNGAP1, both human and animal model studies point to arousal pathways as playing an important role in context-dependent hyperactivity.…”

Section: Discussionmentioning

confidence: 99%

Context-dependent hyperactivity insyngap1aandsyngap1bzebrafish autism models

Sumathipala,

Khan,

Kozol

et al. 2023

Preprint

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Background and Aims: SYNGAP1 disorder is a prevalent genetic form of Autism Spectrum Disorder and Intellectual Disability (ASD/ID) and is caused by de novo or inherited mutations in one copy of the SYNGAP1 gene. In addition to ASD/ID, SYNGAP1 disorder is associated with comorbid symptoms including treatment-resistant-epilepsy, sleep disturbances, and gastrointestinal distress. Mechanistic links between these diverse symptoms and SYNGAP1 variants remain obscure, therefore, our goal was to generate a zebrafish model in which this range of symptoms can be studied. Methods: We used CRISPR/Cas9 to introduce frameshift mutations in the syngap1a and syngap1b zebrafish duplicates (syngap1ab) and validated these stable models for Syngap1 loss-of-function. Because SYNGAP1 is extensively spliced, we mapped splice variants to the two zebrafish syngap1a and b genes and identified mammalian-like isoforms. We then quantified locomotory behaviors in zebrafish syngap1ab larvae under three conditions that normally evoke different arousal states in wild type larvae: aversive, high-arousal acoustic, medium-arousal dark, and low-arousal light stimuli. Results: We show that CRISPR/Cas9 indels in zebrafish syngap1a and syngap1b produced loss-of-function alleles at RNA and protein levels. Our analyses of zebrafish Syngap1 isoforms showed that, as in mammals, zebrafish Syngap1 N- and C-termini are extensively spliced. We identified a zebrafish syngap1 α1-like variant that maps exclusively to the syngap1b gene. Quantifying locomotor behaviors showed that syngap1ab larvae are hyperactive compared to wild type but to differing degrees depending on the stimulus. Hyperactivity was most pronounced in low arousal settings, with overall movement increasing with the number of mutant syngap1 alleles. Conclusions: Our data support mutations in zebrafish syngap1ab as causal for hyperactivity associated with elevated arousal that is especially pronounced in low-arousal environments.

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“…Similarly, a previous study identified distinct and overlapping phenotypes at the level of behavior, brain structure and circuitry by analyzing the function of 10 autism genes in zebrafish. The study observed that the forebrain contributed most to brain size differences between ASD genes, that brain activity phenotypes were concentrated in regions involved in sensory‐motor control, that dopaminergic and microglia abnormalities were the confluence of two genes (SCN2A and DYRK1A), and implied that neuroimmune dysfunction was associated with autism biology 151 . In addition, Willsey et al.…”

Section: Potential Pathogenesis Of Asdmentioning

confidence: 99%

“…The findings suggested that ASD‐associated susceptibility genes ultimately converge on common signaling pathways and that these convergence sites are key to understand ASD pathology. Therefore, categorizing genes based on shared biology despite their heterogeneity might represent a path toward precision medicine in ASD, bridging the gap between gene discovery and actionable biological mechanisms 151 …”

Section: Potential Pathogenesis Of Asdmentioning

confidence: 99%

Autism spectrum disorder: pathogenesis, biomarker, and intervention therapy

Zhuang,

Liang,

et al. 2024

MedComm

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

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High-throughput functional analysis of autism genes in zebrafish identifies convergence in dopaminergic and neuroimmune pathways

Cited by 22 publications

References 99 publications

Autism genes converge on microtubule biology and RNA-binding proteins during excitatory neurogenesis

Autism genes converge on microtubule biology and RNA-binding proteins during excitatory neurogenesis

Context-dependent hyperactivity insyngap1aandsyngap1bzebrafish autism models

Autism spectrum disorder: pathogenesis, biomarker, and intervention therapy

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