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• W3133598085 abstract "Willsey et al. dissect phenotypes associated with in vivo disruption of ten ASD-associated genes using a hypothesis-free, parallelized approach in Xenopus tropicalis. These studies continue to implicate cortical neurons in ASD pathogenesis and suggest a convergence on functions related to neurogenesis. Willsey et al. dissect phenotypes associated with in vivo disruption of ten ASD-associated genes using a hypothesis-free, parallelized approach in Xenopus tropicalis. These studies continue to implicate cortical neurons in ASD pathogenesis and suggest a convergence on functions related to neurogenesis. For many years in human genetics, the search for specific genes associated with autism spectrum disorder (ASD) and related neurodevelopmental disorders (NDDs) was a daunting challenge. As some of the barriers to gene discovery have dissolved with the power of new genomics technologies, large-scale studies have unambiguously identified hundreds of genes contributing risk to ASD and more broadly defined NDDs (Kaplanis et al., 2020Kaplanis J. Samocha K.E. Wiel L. Zhang Z. Arvai K.J. Eberhardt R.Y. Gallone G. Lelieveld S.H. Martin H.C. McRae J.F. et al.Deciphering Developmental Disorders StudyEvidence for 28 genetic disorders discovered by combining healthcare and research data.Nature. 2020; 586: 757-762Crossref PubMed Scopus (59) Google Scholar; Satterstrom et al., 2020Satterstrom F.K. Kosmicki J.A. Wang J. Breen M.S. De Rubeis S. An J.Y. Peng M. Collins R. Grove J. Klei L. et al.Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism.Cell. 2020; 180: 568-584Abstract Full Text Full Text PDF PubMed Scopus (447) Google Scholar). This progress on “what” genes contribute to the etiology of ASD has now raised the critical questions surrounding “when,” “where,” and “how” these disrupted genes exert influence. Chromatin modification, transcriptional regulation, and neuronal communication pathways have been repeatedly implicated in ASD from genetic studies, with more recent analyses also suggesting an involvement of cytoskeleton genes (Moyses-Oliveira et al., 2020Moyses-Oliveira M. Yadav R. Erdin S. Talkowski M.E. New gene discoveries highlight functional convergence in autism and related neurodevelopmental disorders.Curr. Opin. Genet. Dev. 2020; 65: 195-206Crossref PubMed Scopus (14) Google Scholar). Deciphering the extent to which these disparate pathways are interconnected to impede neurodevelopment has thus become a major challenge for the field. Isolating the precise genes that act as regulatory nodes could contribute substantial new insights into NDD neurobiology and pathogenesis. Multiple studies of gene co-expression patterns during fetal development have suggested disruption of specific regions, cell types, and developmental trajectories in ASD (Li et al., 2018Li M. Santpere G. Imamura Kawasawa Y. Evgrafov O.V. Gulden F.O. Pochareddy S. Sunkin S.M. Li Z. Shin Y. Zhu Y. et al.BrainSpan ConsortiumPsychENCODE ConsortiumPsychENCODE Developmental SubgroupIntegrative functional genomic analysis of human brain development and neuropsychiatric risks.Science. 2018; 362: eaat7615Crossref PubMed Scopus (209) Google Scholar; Walker et al., 2019Walker R.L. Ramaswami G. Hartl C. Mancuso N. Gandal M.J. de la Torre-Ubieta L. Pasaniuc B. Stein J.L. Geschwind D.H. Genetic Control of Expression and Splicing in Developing Human Brain Informs Disease Mechanisms.Cell. 2019; 179: 750-771Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar; Willsey et al., 2013Willsey A.J. Sanders S.J. Li M. Dong S. Tebbenkamp A.T. Muhle R.A. Reilly S.K. Lin L. Fertuzinhos S. Miller J.A. et al.Coexpression networks implicate human midfetal deep cortical projection neurons in the pathogenesis of autism.Cell. 2013; 155: 997-1007Abstract Full Text Full Text PDF PubMed Scopus (521) Google Scholar); however, a systematic in vivo screen of functional convergence from direct disruption of ASD genes has largely been intractable due to inherent limitations in perturbing an intact biological system. In this issue of Neuron, a series of studies from Willsey et al. systematically queried the function of ten genes with strong evidence of association to ASD in a hypothesis-free, parallelized in vivo approach using the model system Xenopus tropicalis (Willsey et al., 2021Willsey H.R. Exner C.R.T. Xu Y. Everitt A. Sun N. Wang B. Dea J. Schmunk G. Zaltsman Y. Teerikorpi N. et al.Parallel in vivo analysis of large-effect autism genes implicates cortical neurogenesis and estrogen in risk and resilience.Neuron. 2021; 109 (this issue): 788-804Abstract Full Text Full Text PDF Scopus (7) Google Scholar). Their approach, designed to identify commonalities in phenotypes or expression patterns following disruption of ASD genes with diverse functions, is aligned with recent studies to explore this question in human neurons in vitro (Cederquist et al., 2020Cederquist G.Y. Tchieu J. Callahan S.J. Ramnarine K. Ryan S. Zhang C. Rittenhouse C. Zeltner N. Chung S.Y. Zhou T. et al.A Multiplex Human Pluripotent Stem Cell Platform Defines Molecular and Functional Subclasses of Autism-Related Genes.Cell Stem Cell. 2020; 27: 35-49Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar) and mouse brains in vivo (Jin et al., 2020Jin X. Simmons S.K. Guo A. Shetty A.S. Ko M. Nguyen L. Jokhi V. Robinson E. Oyler P. Curry N. et al.In vivo Perturb-Seq reveals neuronal and glial abnormalities associated with autism risk genes.Science. 2020; 370: eaaz6063Crossref PubMed Scopus (23) Google Scholar). These isogenic studies offer insights into the impact of perturbation of ASD risk genes on neurogenesis while minimizing experimental variability. The distinguishing attribute of the X. tropicalis model is that it offers the opportunity for unilateral mutagenesis to facilitate direct comparison of mutant and control halves of the brain within the same animal. As shown in Figure 1 in Willsey et al., 2021Willsey H.R. Exner C.R.T. Xu Y. Everitt A. Sun N. Wang B. Dea J. Schmunk G. Zaltsman Y. Teerikorpi N. et al.Parallel in vivo analysis of large-effect autism genes implicates cortical neurogenesis and estrogen in risk and resilience.Neuron. 2021; 109 (this issue): 788-804Abstract Full Text Full Text PDF Scopus (7) Google Scholar, transcriptome profiling during X. tropicalis development also enables inference into key points of spatial and temporal convergence identified in fetal studies of ASD risk genes in human neurodevelopment (Li et al., 2018Li M. Santpere G. Imamura Kawasawa Y. Evgrafov O.V. Gulden F.O. Pochareddy S. Sunkin S.M. Li Z. Shin Y. Zhu Y. et al.BrainSpan ConsortiumPsychENCODE ConsortiumPsychENCODE Developmental SubgroupIntegrative functional genomic analysis of human brain development and neuropsychiatric risks.Science. 2018; 362: eaat7615Crossref PubMed Scopus (209) Google Scholar; Walker et al., 2019Walker R.L. Ramaswami G. Hartl C. Mancuso N. Gandal M.J. de la Torre-Ubieta L. Pasaniuc B. Stein J.L. Geschwind D.H. Genetic Control of Expression and Splicing in Developing Human Brain Informs Disease Mechanisms.Cell. 2019; 179: 750-771Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar; Willsey et al., 2013Willsey A.J. Sanders S.J. Li M. Dong S. Tebbenkamp A.T. Muhle R.A. Reilly S.K. Lin L. Fertuzinhos S. Miller J.A. et al.Coexpression networks implicate human midfetal deep cortical projection neurons in the pathogenesis of autism.Cell. 2013; 155: 997-1007Abstract Full Text Full Text PDF PubMed Scopus (521) Google Scholar). The ten ASD risk genes manipulated by Willsey et al. included the X. tropicalis orthologs of five human genes involved in chromatin modification and transcriptional regulation (CHD8, CHD2, ARID1B, ADNP, and POGZ), four genes related to synaptic function (SCN2A, NRXN1, SYNGAP1, and ANK2), and one gene associated with microtubule function and signaling pathways (DYRK1A). Importantly, they also examined six independent genes as negative controls. All ten ASD risk genes were expressed during neurogenesis in the Xenopus telencephalon, and disruption of all ten led to changes in telencephalic size. Remarkably, independent of the impact on brain size, quantifying the ratio of proliferating cell nuclear antigen (PCNA) versus vesicular glutamate transporter 1 (VGlut1) staining revealed that CRISPR perturbation of every gene resulted in an increased ratio of neural progenitor cells (NPCs) to differentiating neurons in the developing telencephalon. These results suggest that all ten of these functionally diverse genes alter brain size upon disruption and converge on a phenotype of increased NPCs compared to mature neurons. The developmental timing of the observed convergent phenotypes in X. tropicalis was aligned with the human mid-prenatal period. To explore the generalizability of these findings in human cells, the authors applied CRISPR interference (CRISPRi) to determine if reduced expression of five of these ASD-associated genes (NRXN1, DYRK1A, CHD2, ADNP, and POGZ) altered the relative proportion of proliferative cells (Ki67+) in human induced pluripotent stem cell (hiPSC)-derived NPCs, observing a statistically significant increase in the relative proportion of Ki67+ proliferative cells in all genes but POGZ, where a non-significant trend was observed. Thus, as in X. tropicalis telencephalon, functionally diverse ASD risk genes affect neurogenesis in human models. Willsey et al. extended these studies to explore convergence from interaction network analyses among 102 genes associated with ASD (Satterstrom et al., 2020Satterstrom F.K. Kosmicki J.A. Wang J. Breen M.S. De Rubeis S. An J.Y. Peng M. Collins R. Grove J. Klei L. et al.Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism.Cell. 2020; 180: 568-584Abstract Full Text Full Text PDF PubMed Scopus (447) Google Scholar). In addition to supporting prior findings, these analyses identified enrichment for ASD risk genes within the mid-prenatal inner subventricular zone (SVZi), an area containing proliferating and differentiating NPCs, consistent with mounting evidence that early corticogenesis is a critical period of ASD etiology. In the final analyses, the study exploits the robust phenotype identified in the X. tropicalis to screen an existing panel of 133 oncology drugs, as these small molecules often target proliferative cells. An initial analysis was performed on the NPC proliferation phenotype in dyrk1a, identifying 17 compounds that either enhanced or suppressed phenotype, three of which were involved in estrogen signaling. Further analyses with additional agonists and antagonists of this pathway were also able to rescue and/or enhance phenotype; moreover, 17-b-estradiol treatment (an endogenous form of estrogen) rescued the effects of DYRK1A inhibition and restored the spatial arrangement of NPCs. A prior chemical screen in zebrafish also observed that estrogens rescued a behavioral phenotype caused by alteration to a recessive ASD risk gene CNTNAP2 (Hoffman et al., 2016Hoffman E.J. Turner K.J. Fernandez J.M. Cifuentes D. Ghosh M. Ijaz S. Jain R.A. Kubo F. Bill B.R. Baier H. et al.Estrogens Suppress a Behavioral Phenotype in Zebrafish Mutants of the Autism Risk Gene, CNTNAP2.Neuron. 2016; 89: 725-733Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar). These analyses of DYRK1A, as well as rescue of additional phenotypes associated with NRXN1 and ADNP disruption, motivated extensive investigation of the balance between estrogen and Sonic hedgehog (Shh) pathways in neurodevelopment. The authors conclude that these studies nominate estrogen as a general resilience factor in ASD. These findings are intriguing in the context of two recent isogenic screens. In one study, a multiplexed hiPSC platform introduced frameshift mutations into 27 ASD genes and defined two subgroups correlated to abnormal WNT signaling: one that inhibited and one that enhanced spontaneous cortical neurogenesis (Cederquist et al., 2020Cederquist G.Y. Tchieu J. Callahan S.J. Ramnarine K. Ryan S. Zhang C. Rittenhouse C. Zeltner N. Chung S.Y. Zhou T. et al.A Multiplex Human Pluripotent Stem Cell Platform Defines Molecular and Functional Subclasses of Autism-Related Genes.Cell Stem Cell. 2020; 27: 35-49Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar). Jin et al. also applied a pooled in vivo CRISPR screening approach to functionally evaluate a set of 35 ASD genes in the developing mouse brain in utero (Jin et al., 2020Jin X. Simmons S.K. Guo A. Shetty A.S. Ko M. Nguyen L. Jokhi V. Robinson E. Oyler P. Curry N. et al.In vivo Perturb-Seq reveals neuronal and glial abnormalities associated with autism risk genes.Science. 2020; 370: eaaz6063Crossref PubMed Scopus (23) Google Scholar). By combining CRISPR-Cas9 and single-cell RNA-sequencing of perturbed cells in the postnatal brain, they identified recurrent neuronal and glial gene modules. Given that a spectrum of developmental and neuropsychiatric phenotypes share some degree of overlapping genetic architectures, there is great value in more expansive isogenic screens, agnostic to previously defined function, as it is likely that we will find additional points of convergence and better resolve the mechanisms responsible. Notably, while extensive evidence links ASD risk genes to both glutamatergic and GABAergic neurons (Satterstrom et al., 2020Satterstrom F.K. Kosmicki J.A. Wang J. Breen M.S. De Rubeis S. An J.Y. Peng M. Collins R. Grove J. Klei L. et al.Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism.Cell. 2020; 180: 568-584Abstract Full Text Full Text PDF PubMed Scopus (447) Google Scholar), all three isogenic studies described here identified functional impacts when manipulating immature NPCs, continuing to implicate critical points of convergence beyond post-mitotic neurons. Are phenotypic abnormalities in these animal models explained by changes in cell type composition and maturity? Is estrogen a general resilience factor with implications for some aspects of heterogenous phenotypes and therapeutic targeting in ASD? These data represent first steps that are far removed from speaking to those broader questions. Nonetheless, they do offer a model system to interrogate molecular mechanisms resulting from perturbation of diverse genes and pathways in vivo. A pressing question that arises is the mechanisms by which these genes ultimately impact synaptic activity, circuit function, and behavior. A powerful aspect to this approach in X. tropicalis, in contrast to pooled CRISPR-based screens, is that it retains the ability to explore the phenotypic impact of gene disruption on circuit function and animal behavior. Moreover, this strategy makes possible the evaluation of in vivo resilience through suppressor screens to further interrogate the functional genomics and modification of complex human traits. As the field continues to leverage CRISPR engineering with increasingly scalable in vitro and in vivo models, we anticipate that important biological insights and novel therapeutic targets will emerge from many points of convergence among genes and functional pathways associated with a spectrum of neuropsychiatric disorders. The Brennand and Talkowski laboratories are supported by National Institute of Health (NIH) grants R56MH101454 , R01MH106056 , R01MH111679 , R01HD096326 , and R01MH115957 . Dr. Talkowski receives research support from Levo Therapeutics. Parallel in vivo analysis of large-effect autism genes implicates cortical neurogenesis and estrogen in risk and resilienceWillsey et al.NeuronJanuary 25, 2021In BriefUsing parallel in vivo analyses and systems biological approaches, Willsey et al. implicate cortical neurogenesis as a point of convergent vulnerability in autism spectrum disorders. They identify estrogen as a resilience factor for multiple, disparate autism genes and reveal a conserved role for estrogen in repressing Sonic hedgehog signaling. Full-Text PDF" @default.
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• W3133598085 title "Xenopus models suggest convergence of gene signatures on neurogenesis in autism" @default.
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