{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T01:43:27Z","timestamp":1771983807632,"version":"3.50.1"},"reference-count":100,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2021,3,23]],"date-time":"2021-03-23T00:00:00Z","timestamp":1616457600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Chromodomain helicase domain 8 (CHD8) is one of the most frequently mutated and most penetrant genes in the autism spectrum disorder (ASD). Individuals with CHD8 mutations show leading symptoms of autism, macrocephaly, and facial dysmorphisms. The molecular and cellular mechanisms underpinning the early onset and development of these symptoms are still poorly understood and prevent timely and more efficient therapies of patients. Progress in this area will require an understanding of \u201cwhen, why and how cells deviate from their normal trajectories\u201d. High-throughput single-cell RNA sequencing (sc-RNAseq) directly quantifies information-bearing RNA molecules that enact each cell\u2019s biological identity. Here, we discuss recent insights from sc-RNAseq of CRISPR\/Cas9-editing of Chd8\/CHD8 during mouse neocorticogenesis and human cerebral organoids. Given that the deregulation of the balance between excitation and inhibition (E\/I balance) in cortical and subcortical circuits is thought to represent a major etiopathogenetic mechanism in ASD, we focus on the question of whether, and to what degree, results from current sc-RNAseq studies support this hypothesis. Beyond that, we discuss the pros and cons of these approaches and further steps to be taken to harvest the full potential of these transformative techniques.<\/jats:p>","DOI":"10.3390\/ijms22063261","type":"journal-article","created":{"date-parts":[[2021,3,23]],"date-time":"2021-03-23T14:08:16Z","timestamp":1616508496000},"page":"3261","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Single-Cell Transcriptomics Supports a Role of CHD8 in Autism"],"prefix":"10.3390","volume":"22","author":[{"given":"Anke","family":"Hoffmann","sequence":"first","affiliation":[{"name":"Translational Research in Psychiatry, Max Planck Institute of Psychiatry, 80804 Munich, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dietmar","family":"Spengler","sequence":"additional","affiliation":[{"name":"Translational Research in Psychiatry, Max Planck Institute of Psychiatry, 80804 Munich, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,3,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1038\/s41586-020-2715-9","article-title":"LifeTime and improving European healthcare through cell-based interceptive medicine","volume":"587","author":"Rajewsky","year":"2020","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1034\/j.1601-183X.2003.00037.x","article-title":"Model of autism: Increased ratio of excitation\/inhibition in key neural systems","volume":"2","author":"Rubenstein","year":"2003","journal-title":"Genes Brain Behav."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1146\/annurev-publhealth-031816-044318","article-title":"The Changing Epidemiology of Autism Spectrum Disorders","volume":"38","author":"Lyall","year":"2017","journal-title":"Annu. Rev. Public Health"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"American Psychiatric Association (2013). Diagnostic and Statistical Manual of Mental Disorders: DSM-5, American Psychiatric Publishing. [5th ed.].","DOI":"10.1176\/appi.books.9780890425596"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1016\/S1474-4422(15)00044-7","article-title":"Gene hunting in autism spectrum disorder: On the path to precision medicine","volume":"14","author":"Geschwind","year":"2015","journal-title":"Lancet Neurol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1038\/ng.3039","article-title":"Most genetic risk for autism resides with common variation","volume":"46","author":"Gaugler","year":"2014","journal-title":"Nat. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1038\/s41588-019-0344-8","article-title":"Identification of common genetic risk variants for autism spectrum disorder","volume":"51","author":"Grove","year":"2019","journal-title":"Nat. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1038\/nature13772","article-title":"Synaptic, transcriptional and chromatin genes disrupted in autism","volume":"515","author":"He","year":"2014","journal-title":"Nature"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1038\/nature13908","article-title":"The contribution of de novo coding mutations to autism spectrum disorder","volume":"515","author":"Iossifov","year":"2014","journal-title":"Nature"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1016\/j.cell.2019.12.036","article-title":"Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism","volume":"180","author":"Satterstrom","year":"2020","journal-title":"Cell"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1016\/j.biopsych.2017.01.009","article-title":"Opposing Effects on NaV1.2 Function Underlie Differences Between SCN2A Variants Observed in Individuals With Autism Spectrum Disorder or Infantile Seizures","volume":"82","author":"Keeshen","year":"2017","journal-title":"Biol. Psychiatry"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/j.cell.2014.06.017","article-title":"Disruptive CHD8 mutations define a subtype of autism early in development","volume":"158","author":"Bernier","year":"2014","journal-title":"Cell"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"850","DOI":"10.1016\/j.cell.2019.07.015","article-title":"Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks","volume":"178","author":"Ruzzo","year":"2019","journal-title":"Cell"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"477","DOI":"10.3389\/fnins.2015.00477","article-title":"Mutations and Modeling of the Chromatin Remodeler CHD8 Define an Emerging Autism Etiology","volume":"9","author":"Barnard","year":"2015","journal-title":"Front. Neurosci."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Hoffmann, A., Ziller, M., and Spengler, D. (2020). Focus on Causality in ESC\/iPSC-Based Modeling of Psychiatric Disorders. Cells, 9.","DOI":"10.3390\/cells9020366"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"481","DOI":"10.3389\/fnmol.2018.00481","article-title":"Common CHD8 Genomic Targets Contrast With Model-Specific Transcriptional Impacts of CHD8 Haploinsufficiency","volume":"11","author":"Wade","year":"2018","journal-title":"Front. Mol. Neurosci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1038\/ng1089","article-title":"Epigenetic regulation of gene expression: How the genome integrates intrinsic and environmental signals","volume":"33","author":"Jaenisch","year":"2003","journal-title":"Nat. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1080\/19491034.2016.1211217","article-title":"Chromatin remodelers: We are the drivers!","volume":"7","author":"Tyagi","year":"2016","journal-title":"Nucleus"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1007\/s11920-012-0255-1","article-title":"Genetic variation in the epigenetic machinery and mental health","volume":"14","author":"Murgatroyd","year":"2012","journal-title":"Curr. Psychiatry Rep."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.tins.2013.11.005","article-title":"A de novo convergence of autism genetics and molecular neuroscience","volume":"37","author":"Krumm","year":"2014","journal-title":"Trends Neurosci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1146\/annurev.biochem.77.062706.153223","article-title":"The biology of chromatin remodeling complexes","volume":"78","author":"Clapier","year":"2009","journal-title":"Annu. Rev. Biochem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1146\/annurev.biochem.76.052305.115300","article-title":"Structure and mechanism of helicases and nucleic acid translocases","volume":"76","author":"Singleton","year":"2007","journal-title":"Annu. Rev. Biochem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"223","DOI":"10.3389\/fpls.2014.00223","article-title":"Transcription regulation by CHD proteins to control plant development","volume":"5","author":"Hu","year":"2014","journal-title":"Front. Plant Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"682","DOI":"10.3389\/fgene.2019.00682","article-title":"Chromatin Remodeling Complex NuRD in Neurodevelopment and Neurodevelopmental Disorders","volume":"10","author":"Hoffmann","year":"2019","journal-title":"Front. Genet."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1016\/j.neuron.2012.04.009","article-title":"De novo gene disruptions in children on the autistic spectrum","volume":"74","author":"Iossifov","year":"2012","journal-title":"Neuron"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1038\/nature11011","article-title":"Patterns and rates of exonic de novo mutations in autism spectrum disorders","volume":"485","author":"Neale","year":"2012","journal-title":"Nature"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1038\/nature10989","article-title":"Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations","volume":"485","author":"Vives","year":"2012","journal-title":"Nature"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1038\/nature10945","article-title":"De novo mutations revealed by whole-exome sequencing are strongly associated with autism","volume":"485","author":"Sanders","year":"2012","journal-title":"Nature"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"5595","DOI":"10.1038\/ncomms6595","article-title":"Recurrent de novo mutations implicate novel genes underlying simplex autism risk","volume":"5","author":"Stessman","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"13316","DOI":"10.1038\/ncomms13316","article-title":"De novo genic mutations among a Chinese autism spectrum disorder cohort","volume":"7","author":"Wang","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1038\/ng.3792","article-title":"Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases","volume":"49","author":"Stessman","year":"2017","journal-title":"Nat. Genet."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1016\/j.cell.2012.03.028","article-title":"Sequencing chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries","volume":"149","author":"Talkowski","year":"2012","journal-title":"Cell"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1038\/s10038-019-0561-0","article-title":"A distinct neurodevelopmental syndrome with intellectual disability, autism spectrum disorder, characteristic facies, and macrocephaly is caused by defects in CHD8","volume":"64","author":"Yasin","year":"2019","journal-title":"J. Hum. Genet."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1007\/s00439-020-02115-9","article-title":"De novo variants in the Helicase-C domain of CHD8 are associated with severe phenotypes including autism, language disability and overgrowth","volume":"139","author":"An","year":"2020","journal-title":"Hum. Genet."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.biopsych.2019.07.020","article-title":"Clinical Phenotypes of Carriers of Mutations in CHD8 or Its Conserved Target Genes","volume":"87","author":"Beighley","year":"2020","journal-title":"Biol. Psychiatry"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1002\/ajmg.c.31749","article-title":"The CHD8 overgrowth syndrome: A detailed evaluation of an emerging overgrowth phenotype in 27 patients","volume":"181","author":"Ostrowski","year":"2019","journal-title":"Am. J. Med. Genet. C Semin. Med. Genet."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1111\/cge.13665","article-title":"Phenotype-to-genotype approach reveals head-circumference-associated genes in an autism spectrum disorder cohort","volume":"97","author":"Wu","year":"2020","journal-title":"Clin. Genet."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1038\/nature07991","article-title":"Parvalbumin neurons and gamma rhythms enhance cortical circuit performance","volume":"459","author":"Sohal","year":"2009","journal-title":"Nature"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1016\/j.neuron.2020.02.015","article-title":"Whole-Neuron Synaptic Mapping Reveals Spatially Precise Excitatory\/Inhibitory Balance Limiting Dendritic and Somatic Spiking","volume":"106","author":"Iascone","year":"2020","journal-title":"Neuron"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1016\/j.neuron.2020.05.015","article-title":"Targeting Homeostatic Synaptic Plasticity for Treatment of Mood Disorders","volume":"106","author":"Kavalali","year":"2020","journal-title":"Neuron"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"146","DOI":"10.2174\/1566524015666150303003028","article-title":"Common mechanisms of excitatory and inhibitory imbalance in schizophrenia and autism spectrum disorders","volume":"15","author":"Gao","year":"2015","journal-title":"Curr. Mol. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"838","DOI":"10.1016\/j.biopsych.2016.05.011","article-title":"Excitation\/Inhibition Imbalance in Animal Models of Autism Spectrum Disorders","volume":"81","author":"Lee","year":"2017","journal-title":"Biol. Psychiatry"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.jpsychires.2018.06.004","article-title":"Excitation-inhibition dysbalance as predictor of autistic phenotypes","volume":"104","author":"Oliveira","year":"2018","journal-title":"J. Psychiatr. Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"20180944","DOI":"10.1259\/bjr.20180944","article-title":"Revisiting the excitation\/inhibition imbalance hypothesis of ASD through a clinical lens","volume":"92","author":"Port","year":"2019","journal-title":"Br. J. Radiol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1186\/s13229-015-0065-5","article-title":"Auditory encoding abnormalities in children with autism spectrum disorder suggest delayed development of auditory cortex","volume":"6","author":"Edgar","year":"2015","journal-title":"Mol. Autism"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1016\/j.nicl.2016.03.021","article-title":"Maturation of auditory neural processes in autism spectrum disorder\u2014A longitudinal MEG study","volume":"11","author":"Port","year":"2016","journal-title":"Neuroimage Clin."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/aur.1260","article-title":"Increased glutamate concentration in the auditory cortex of persons with autism and first-degree relatives: A (1)H-MRS study","volume":"6","author":"Brown","year":"2013","journal-title":"Autism Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1038\/s41398-018-0155-1","article-title":"Glutamate and GABA in autism spectrum disorder-a translational magnetic resonance spectroscopy study in man and rodent models","volume":"8","author":"Horder","year":"2018","journal-title":"Transl. Psychiatry"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"152","DOI":"10.2478\/v10039-012-0014-x","article-title":"Metabolite alterations in autistic children: A 1H MR spectroscopy study","volume":"57","author":"Kubas","year":"2012","journal-title":"Adv. Med. Sci."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1002\/(SICI)1099-1492(199810)11:6<266::AID-NBM530>3.0.CO;2-J","article-title":"Simultaneous in vivo spectral editing and water suppression","volume":"11","author":"Mescher","year":"1998","journal-title":"NMR Biomed."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1008","DOI":"10.1016\/j.cell.2013.10.031","article-title":"Integrative functional genomic analyses implicate specific molecular pathways and circuits in autism","volume":"155","author":"Parikshak","year":"2013","journal-title":"Cell"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1016\/j.cell.2013.10.020","article-title":"Coexpression networks implicate human midfetal deep cortical projection neurons in the pathogenesis of autism","volume":"155","author":"Willsey","year":"2013","journal-title":"Cell"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.biopsych.2016.12.030","article-title":"Imaging Genetics and Genomics in Psychiatry: A Critical Review of Progress and Potential","volume":"82","author":"Bogdan","year":"2017","journal-title":"Biol. Psychiatry"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Berto, S., Treacher, A., Caglayan, E., Luo, D., Haney, J.R., Gandal, M.J., Geschwind, D.H., Montillo, A., and Konopka, G. (2021). Association between resting-state functional brain connectivity and gene expression is altered in autism spectrum disorder. medRxiv.","DOI":"10.1101\/2021.01.07.21249281"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1016\/j.celrep.2017.03.052","article-title":"Chd8 mutation leads to autistic-like behaviors and impaired striatal circuits","volume":"19","author":"Platt","year":"2017","journal-title":"Cell Rep."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1218","DOI":"10.1038\/s41593-018-0208-z","article-title":"Sexually dimorphic behavior, neuronal activity, and gene expression in Chd8-mutant mice","volume":"21","author":"Jung","year":"2018","journal-title":"Nat. Neurosci."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Ellingford, R.A., de Meritens, E.R., Shaunak, R., Naybour, L., Basson, M.A., and Andreae, L.C. (2020). Cell-type-specific synaptic imbalance and disrupted homeostatic plasticity in cortical circuits of ASD-associated Chd8 haploinsufficient mice. bioRxiv.","DOI":"10.1101\/2020.05.14.093187"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.neuron.2020.12.010","article-title":"Single-Cell Sequencing of Brain Cell Transcriptomes and Epigenomes","volume":"109","author":"Armand","year":"2021","journal-title":"Neuron"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"eaaz6063","DOI":"10.1126\/science.aaz6063","article-title":"In vivo Perturb-Seq reveals neuronal and glial abnormalities associated with autism risk genes","volume":"370","author":"Jin","year":"2020","journal-title":"Science"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"E8246","DOI":"10.1073\/pnas.1802620115","article-title":"Oligodendrocyte precursor survival and differentiation requires chromatin remodeling by Chd7 and Chd8","volume":"115","author":"Marie","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1016\/j.devcel.2018.05.022","article-title":"Dual Requirement of CHD8 for Chromatin Landscape Establishment and Histone Methyltransferase Recruitment to Promote CNS Myelination and Repair","volume":"45","author":"Zhao","year":"2018","journal-title":"Dev. Cell"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.pnpbp.2015.11.005","article-title":"A proton spectroscopy study of white matter in children with autism","volume":"66","author":"Hardan","year":"2016","journal-title":"Prog. Neuropsychopharmacol. Biol. Psychiatry"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1016\/j.neuroimage.2017.12.056","article-title":"Early nutrition influences developmental myelination and cognition in infants and young children","volume":"178","author":"Deoni","year":"2018","journal-title":"Neuroimage"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1111\/cge.13554","article-title":"The clinical presentation caused by truncating CHD8 variants","volume":"96","author":"Douzgou","year":"2019","journal-title":"Clin. Genet."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Hoffmann, A., and Spengler, D. (2021). Chromatin Remodeler CHD8 in Autism and Brain Development. J. Clin. Med., 10.","DOI":"10.3390\/jcm10020366"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1038\/nrneurol.2017.45","article-title":"Human induced pluripotent stem cells for modelling neurodevelopmental disorders","volume":"13","author":"Ardhanareeswaran","year":"2017","journal-title":"Nat. Rev. Neurol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.1038\/s41593-018-0188-z","article-title":"Fragility and volatility of structural hubs in the human connectome","volume":"21","author":"Gollo","year":"2018","journal-title":"Nat. Neurosci."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1496","DOI":"10.1038\/s41593-020-00730-3","article-title":"Brain organoids for the study of human neurobiology at the interface of in vitro and in vivo","volume":"23","author":"Chiaradia","year":"2020","journal-title":"Nat. Neurosci."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1682","DOI":"10.1016\/j.celrep.2020.01.038","article-title":"Synthetic Analyses of Single-Cell Transcriptomes from Multiple Brain Organoids and Fetal Brain","volume":"30","author":"Tanaka","year":"2020","journal-title":"Cell Rep."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1038\/nature22047","article-title":"Cell diversity and network dynamics in photosensitive human brain organoids","volume":"545","author":"Quadrato","year":"2017","journal-title":"Nature"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1016\/j.stem.2020.02.002","article-title":"Sliced Human Cortical Organoids for Modeling Distinct Cortical Layer Formation","volume":"26","author":"Qian","year":"2020","journal-title":"Cell Stem Cell"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1038\/s41586-019-1289-x","article-title":"Individual brain organoids reproducibly form cell diversity of the human cerebral cortex","volume":"570","author":"Velasco","year":"2019","journal-title":"Nature"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1186\/s13229-017-0124-1","article-title":"CRISPR\/Cas9-mediated heterozygous knockout of the autism gene CHD8 and characterization of its transcriptional networks in cerebral organoids derived from iPS cells","volume":"8","author":"Wang","year":"2017","journal-title":"Mol. Autism"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1186\/s13229-015-0048-6","article-title":"CRISPR\/Cas9-mediated heterozygous knockout of the autism gene CHD8 and characterization of its transcriptional networks in neurodevelopment","volume":"6","author":"Wang","year":"2015","journal-title":"Mol. Autism"},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Hoffmann, A., Sportelli, V., Ziller, M., and Spengler, D. (2017). Switch-Like Roles for Polycomb Proteins from Neurodevelopment to Neurodegeneration. Epigenomes, 1.","DOI":"10.3390\/epigenomes1030021"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1366","DOI":"10.1002\/ajmg.a.31252","article-title":"Dlx homeobox gene control of mammalian limb and craniofacial development","volume":"140","author":"Kraus","year":"2006","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1470","DOI":"10.1101\/gad.1416106","article-title":"The Evf-2 noncoding RNA is transcribed from the Dlx-5\/6 ultraconserved region and functions as a Dlx-2 transcriptional coactivator","volume":"20","author":"Feng","year":"2006","journal-title":"Genes Dev."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"2675","DOI":"10.1523\/JNEUROSCI.3110-10.2011","article-title":"Wnt5a is a transcriptional target of Dlx homeogenes and promotes differentiation of interneuron progenitors in vitro and in vivo","volume":"31","author":"Paina","year":"2011","journal-title":"J. Neurosci."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"3089","DOI":"10.1242\/dev.051052","article-title":"An SNP in an ultraconserved regulatory element affects Dlx5\/Dlx6 regulation in the forebrain","volume":"137","author":"Poitras","year":"2010","journal-title":"Development"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1016\/j.cell.2015.06.034","article-title":"FOXG1-Dependent Dysregulation of GABA\/Glutamate Neuron Differentiation in Autism Spectrum Disorders","volume":"162","author":"Mariani","year":"2015","journal-title":"Cell"},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Villa, C.E., Cheroni, C., L\u00f3pez-T\u00f3bon, A., Dotter, C.P., Oliveira, B., Sacco, R., Yahya, A.C., Morandell, J., Gabriele, M., and Sommer, C. (2020). CHD8 haploinsufficiency alters the developmental trajectories of human excitatory and inhibitory neurons linking autism phenotypes with transient cellular defects. bioRxiv.","DOI":"10.1101\/2020.11.26.399469"},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Benito-Kwiecinski, S., Giandomenico, S.L., Sutcliffe, M., Riis, E.S., Freire-Pritchett, P., Kelava, I., Wunderlich, S., Martin, U., Wray, G., and Lancaster, M.A. (2020). An early cell shape transition drives evolutionary expansion of the human forebrain. bioRxiv.","DOI":"10.1101\/2020.07.04.188078"},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Hurley, S., Mohan, C., Suetterlin, P., Ellegood, J., Rudari, F., Lerch, J.P., Fernandes, C., and Basson, M.A. (2018). Non-monotonic regulation of gene expression, neural progenitor fate and brain growth by the chromatin remodeller CHD8. bioRxiv.","DOI":"10.1101\/469031"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1038\/s41380-019-0426-0","article-title":"Excitation-inhibition balance as a framework for investigating mechanisms in neuropsychiatric disorders","volume":"24","author":"Sohal","year":"2019","journal-title":"Mol. Psychiatry"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1038\/nature10110","article-title":"Transcriptomic analysis of autistic brain reveals convergent molecular pathology","volume":"474","author":"Voineagu","year":"2011","journal-title":"Nature"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"5748","DOI":"10.1038\/ncomms6748","article-title":"Transcriptome analysis reveals dysregulation of innate immune response genes and neuronal activity-dependent genes in autism","volume":"5","author":"Gupta","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"9","DOI":"10.7554\/eLife.52904","article-title":"A fully automated high-throughput workflow for 3D-based chemical screening in human midbrain organoids","volume":"9","author":"Renner","year":"2020","journal-title":"Elife"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1038\/s41380-018-0029-1","article-title":"New considerations for hiPSC-based models of neuropsychiatric disorders","volume":"24","author":"Hoffman","year":"2018","journal-title":"Mol. Psychiatry"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1038\/nature18637","article-title":"A comprehensive transcriptional map of primate brain development","volume":"535","author":"Bakken","year":"2016","journal-title":"Nature"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1038\/s41586-019-1506-7","article-title":"Conserved cell types with divergent features in human versus mouse cortex","volume":"573","author":"Hodge","year":"2019","journal-title":"Nature"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1016\/j.cell.2012.02.052","article-title":"Large-scale cellular-resolution gene profiling in human neocortex reveals species-specific molecular signatures","volume":"149","author":"Zeng","year":"2012","journal-title":"Cell"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1038\/nrn2759","article-title":"Mechanisms underlying spontaneous patterned activity in developing neural circuits","volume":"11","author":"Blankenship","year":"2010","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1016\/j.stem.2019.08.002","article-title":"Complex Oscillatory Waves Emerging from Cortical Organoids Model Early Human Brain Network Development","volume":"25","author":"Trujillo","year":"2019","journal-title":"Cell Stem Cell"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1282","DOI":"10.1016\/j.tibtech.2019.05.009","article-title":"Optogenetics in the Era of Cerebral Organoids","volume":"37","author":"Shiri","year":"2019","journal-title":"Trends Biotechnol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1038\/nbt.4127","article-title":"An in vivo model of functional and vascularized human brain organoids","volume":"36","author":"Mansour","year":"2018","journal-title":"Nat. Biotechnol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"eaau1810","DOI":"10.1126\/science.aau1810","article-title":"In vivo modeling of human neuron dynamics and Down syndrome","volume":"362","author":"Real","year":"2018","journal-title":"Science"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/j.stem.2017.06.012","article-title":"Human iPSC Glial Mouse Chimeras Reveal Glial Contributions to Schizophrenia","volume":"21","author":"Windrem","year":"2017","journal-title":"Cell Stem Cell"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/j.cell.2013.06.045","article-title":"Glia keep synapse distribution under wraps","volume":"154","author":"Clarke","year":"2013","journal-title":"Cell"},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Hoffmann, A., Ziller, M., and Spengler, D. (2018). Childhood-Onset Schizophrenia: Insights from Induced Pluripotent Stem Cells. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19123829"},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"Hoffmann, A., Ziller, M., and Spengler, D. (2019). Progress in iPSC-Based Modeling of Psychiatric Disorders. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20194896"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/6\/3261\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:39:39Z","timestamp":1760161179000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/6\/3261"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,23]]},"references-count":100,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2021,3]]}},"alternative-id":["ijms22063261"],"URL":"https:\/\/doi.org\/10.3390\/ijms22063261","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,23]]}}}