Parallel in vivo analysis of large-effect autism genes implicates cortical neurogenesis and estrogen in risk and resilience

Willsey, Helen Rankin; Exner, Cameron R.T.; Xu, Yizhen; Everitt, Amanda; Sun, Nawei; Wang, Belinda; Dea, Jeanselle; Schmunk, Galina; Zaltsman, Yefim; Teerikorpi, Nia; Kim, Albert; Anderson, Aoife S.; Shin, David; Seyler, Meghan; Nowakowski, Tomasz J.; Harland, Richard M.; Willsey, A. Jeremy; State, Matthew W.

doi:10.1016/j.neuron.2021.01.002

Cited by 68 publications

(76 citation statements)

References 105 publications

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“…One of the most notable examples is the "extreme male brain" theory (discussed below). In addition, studies investigating the function of ASD risk genes in preclinical systems, including one from our group, identified estrogens as potential modulators of ASD gene-associated cellular and behavioral phenotypes (8,9,48). However, genes that directly affect sex steroid hormone signaling, e.g., estrogen or androgen receptors, have not been identified among the strongest ASDassociated genes (e.g., ESR1, which encodes Estrogen Receptor 1, is not listed in SFARI Gene; AR, encoding Androgen Receptor, has a SFARI gene score of 3), suggesting that estrogens and/or androgens may be acting indirectly to modulate signaling pathway deficits resulting from ASD risk gene mutations.…”

Section: The Female Protective Effect In Asdmentioning

confidence: 99%

“…Interestingly, recent preclinical studies investigating the function of ASD risk genes in distinct model systems, including one from our group, found that estrogens might play a modulatory role in signaling pathways related to ASD and other neurodevelopmental disorders (Table 2) (8,9,48,72). First, our group investigated the ASD and epilepsy risk gene, Contactin Associated Protein-like 2 (CNTNAP2), and identified estrogenic compounds in an unbiased screen as a suppressor of a behavioral phenotype in zebrafish lacking the function of this gene (8).…”

Section: Functional Studies Of Asd Risk Genes Identify Estrogens As Potential Modulatorsmentioning

confidence: 99%

“…Remarkably, another recent study also found that estrogens might act as modulators of cell proliferation phenotypes across multiple ASD risk genes (9). Willsey et al (9) performed an in vivo CRISPR screen in Xenopus tropicalis targeting 10 high confidence ASD risk genes. By capitalizing on a unique feature of Xenopus, in which it is possible to generate unilateral mutants by introducing CRISPRs into one cell at the two-cell stage and compare phenotypes on either side of the midline at later stages, the authors found that disruption of high confidence ASD risk genes resulted in altered telencephalon size as well as an increased ratio of neural progenitor cells to neurons in this region (9).…”

Section: Functional Studies Of Asd Risk Genes Identify Estrogens As Potential Modulatorsmentioning

confidence: 99%

“…Willsey et al (9) performed an in vivo CRISPR screen in Xenopus tropicalis targeting 10 high confidence ASD risk genes. By capitalizing on a unique feature of Xenopus, in which it is possible to generate unilateral mutants by introducing CRISPRs into one cell at the two-cell stage and compare phenotypes on either side of the midline at later stages, the authors found that disruption of high confidence ASD risk genes resulted in altered telencephalon size as well as an increased ratio of neural progenitor cells to neurons in this region (9). Disruption of ASD risk genes in human induced pluripotent stem cell (iPSC)-derived neural progenitor cells (NPCs) using CRISPR interference (CRISPRi) also led to an increase in the proportion of proliferative cells, which together with the findings in Xenopus, suggests that dysregulated neurogenesis may represent a convergent pathway linking these genes (9).…”

Section: Functional Studies Of Asd Risk Genes Identify Estrogens As Potential Modulatorsmentioning

confidence: 99%

“…While the etiology of the female protective effect in ASD is unknown, one hypothesis is that differential exposure to sex steroid hormones may be a contributing factor (7). Interestingly, recent studies analyzing the function of ASD risk genes in animal models, including one from our group, independently identified estrogens as suppressors of ASD gene-associated cellular and behavioral phenotypes, implicating estrogens as potential modulators of biological pathways relevant to ASD (8,9). However, studies directly assessing the role of estrogens in ASDs, both in clinical and preclinical models, are limited.…”

Section: Introductionmentioning

confidence: 99%

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Signaling Pathways and Sex Differential Processes in Autism Spectrum Disorder

2021

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Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders associated with deficits in social communication and restrictive, repetitive patterns of behavior, that affect up to 1 in 54 children. ASDs clearly demonstrate a male bias, occurring ~4 times more frequently in males than females, though the basis for this male predominance is not well-understood. In recent years, ASD risk gene discovery has accelerated, with many whole-exome sequencing studies identifying genes that converge on common pathways, such as neuronal communication and regulation of gene expression. ASD genetics studies have suggested that there may be a “female protective effect,” such that females may have a higher threshold for ASD risk, yet its etiology is not well-understood. Here, we review common biological pathways implicated by ASD genetics studies as well as recent analyses of sex differential processes in ASD using imaging genomics, transcriptomics, and animal models. Additionally, we discuss recent investigations of ASD risk genes that have suggested a potential role for estrogens as modulators of biological pathways in ASD, and highlight relevant molecular and cellular pathways downstream of estrogen signaling as potential avenues for further investigation.

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Section: The Female Protective Effect In Asdmentioning

confidence: 99%

Section: Functional Studies Of Asd Risk Genes Identify Estrogens As Potential Modulatorsmentioning

confidence: 99%

Section: Functional Studies Of Asd Risk Genes Identify Estrogens As Potential Modulatorsmentioning

confidence: 99%

Section: Functional Studies Of Asd Risk Genes Identify Estrogens As Potential Modulatorsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Signaling Pathways and Sex Differential Processes in Autism Spectrum Disorder

2021

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Autism Spectrum Disorder

Hirota

King

2023

JAMA

198

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ImportanceAutism spectrum disorder (ASD), characterized by deficits in social communication and the presence of restricted, repetitive behaviors or interests, is a neurodevelopmental disorder affecting approximately 2.3% children aged 8 years in the US and approximately 2.2% of adults. This review summarizes evidence on the diagnosis and treatment of ASD.ObservationsThe estimated prevalence of ASD has been increasing in the US, from 1.1% in 2008 to 2.3% in 2018, which is likely associated with changes in diagnostic criteria, improved performance of screening and diagnostic tools, and increased public awareness. No biomarkers specific to the diagnosis of ASD have been identified. Common early signs and symptoms of ASD in a child’s first 2 years of life include no response to name when called, no or limited use of gestures in communication, and lack of imaginative play. The criterion standard for the diagnosis of ASD is a comprehensive evaluation with a multidisciplinary team of clinicians and is based on semistructured direct observation of the child’s behavior and semistructured caregiver interview focused on the individual’s development and behaviors using standardized measures, such as the Autism Diagnostic Observation Schedule-Second Edition and the Autism Diagnostic Interview. These diagnostic measures have sensitivity of 91% and 80% and specificity of 76% and 72%, respectively. Compared with people without ASD, individuals with ASD have higher rates of depression (20% vs 7%), anxiety (11% vs 5%), sleep difficulties (13% vs 5%), and epilepsy (21% with co-occurring intellectual disability vs 0.8%). Intensive behavioral interventions, such as the Early Start Denver Model, are beneficial in children 5 years or younger for improvement in language, play, and social communication (small to medium effect size based on standardized mean difference). Pharmacotherapy is indicated for co-occurring psychiatric conditions, such as emotion dysregulation or attention-deficit/hyperactivity disorder. Risperidone and aripiprazole can improve irritability and aggression (standardized mean difference of 1.1, consistent with a large effect size) compared with placebo. Psychostimulants are effective for attention-deficit/hyperactivity disorder (standardized mean difference of 0.6, consistent with a moderate effect size) compared with placebo. These medications are associated with adverse effects including, most commonly, changes in appetite, weight, and sleep.Conclusions and RelevanceASD affects approximately 2.3% of children aged 8 years and approximately 2.2% of adults in the US. First-line therapy consists of behavioral interventions, while co-occurring psychiatric conditions, such as anxiety or aggression, may be treated with specific behavioral therapy or medication.

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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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Parallel in vivo analysis of large-effect autism genes implicates cortical neurogenesis and estrogen in risk and resilience

Cited by 68 publications

References 105 publications

Signaling Pathways and Sex Differential Processes in Autism Spectrum Disorder

Signaling Pathways and Sex Differential Processes in Autism Spectrum Disorder

Autism Spectrum Disorder

Autism spectrum disorder: pathogenesis, biomarker, and intervention therapy

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