{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:22:07Z","timestamp":1790814127903,"version":"4.1.0"},"reference-count":107,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2022,7,7]],"date-time":"2022-07-07T00:00:00Z","timestamp":1657152000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ile-de-France Regional Council","award":["ANSES-21-RF-24"],"award-info":[{"award-number":["ANSES-21-RF-24"]}]},{"name":"Ile-de-France Regional Council","award":["ANR-20-CE16-0004-01"],"award-info":[{"award-number":["ANR-20-CE16-0004-01"]}]},{"name":"Inserm","award":["ANSES-21-RF-24"],"award-info":[{"award-number":["ANSES-21-RF-24"]}]},{"name":"Inserm","award":["ANR-20-CE16-0004-01"],"award-info":[{"award-number":["ANR-20-CE16-0004-01"]}]},{"name":"Institut Curie","award":["ANSES-21-RF-24"],"award-info":[{"award-number":["ANSES-21-RF-24"]}]},{"name":"Institut Curie","award":["ANR-20-CE16-0004-01"],"award-info":[{"award-number":["ANR-20-CE16-0004-01"]}]},{"name":"Universit\u00e9 Paris Cit\u00e9","award":["ANSES-21-RF-24"],"award-info":[{"award-number":["ANSES-21-RF-24"]}]},{"name":"Universit\u00e9 Paris Cit\u00e9","award":["ANR-20-CE16-0004-01"],"award-info":[{"award-number":["ANR-20-CE16-0004-01"]}]},{"name":"PNREST Anses","award":["ANSES-21-RF-24"],"award-info":[{"award-number":["ANSES-21-RF-24"]}]},{"name":"PNREST Anses","award":["ANR-20-CE16-0004-01"],"award-info":[{"award-number":["ANR-20-CE16-0004-01"]}]},{"name":"ANR","award":["ANSES-21-RF-24"],"award-info":[{"award-number":["ANSES-21-RF-24"]}]},{"name":"ANR","award":["ANR-20-CE16-0004-01"],"award-info":[{"award-number":["ANR-20-CE16-0004-01"]}]},{"name":"Ville de Paris \u201cEmergences\u201d program","award":["ANSES-21-RF-24"],"award-info":[{"award-number":["ANSES-21-RF-24"]}]},{"name":"Ville de Paris \u201cEmergences\u201d program","award":["ANR-20-CE16-0004-01"],"award-info":[{"award-number":["ANR-20-CE16-0004-01"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>How the brain develops and achieves its final size is a fascinating issue that questions cortical evolution across species and man\u2019s place in the animal kingdom. Although animal models have so far been highly valuable in understanding the key steps of cortical development, many human specificities call for appropriate models. In particular, microcephaly, a neurodevelopmental disorder that is characterized by a smaller head circumference has been challenging to model in mice, which often do not fully recapitulate the human phenotype. The relatively recent development of brain organoid technology from induced pluripotent stem cells (iPSCs) now makes it possible to model human microcephaly, both due to genetic and environmental origins, and to generate developing cortical tissue from the patients themselves. These 3D tissues rely on iPSCs differentiation into cortical progenitors that self-organize into neuroepithelial rosettes mimicking the earliest stages of human neurogenesis in vitro. Over the last ten years, numerous protocols have been developed to control the identity of the induced brain areas, the reproducibility of the experiments and the longevity of the cultures, allowing analysis of the later stages. In this review, we describe the different approaches that instruct human iPSCs to form cortical organoids, summarize the different microcephalic conditions that have so far been modeled by organoids, and discuss the relevance of this model to decipher the cellular and molecular mechanisms of primary and secondary microcephalies.<\/jats:p>","DOI":"10.3390\/cells11142135","type":"journal-article","created":{"date-parts":[[2022,7,7]],"date-time":"2022-07-07T07:51:56Z","timestamp":1657180316000},"page":"2135","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Cortical Organoids to Model Microcephaly"],"prefix":"10.3390","volume":"11","author":[{"given":"Sarah","family":"Farcy","sequence":"first","affiliation":[{"name":"Institut Curie, PSL Research University, CNRS UMR144, F-75005 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Albert","sequence":"additional","affiliation":[{"name":"NeuroDiderot, Inserm, Universit\u00e9 Paris Cit\u00e9, F-75019 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0909-4221","authenticated-orcid":false,"given":"Pierre","family":"Gressens","sequence":"additional","affiliation":[{"name":"NeuroDiderot, Inserm, Universit\u00e9 Paris Cit\u00e9, F-75019 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandre D.","family":"Baffet","sequence":"additional","affiliation":[{"name":"Institut Curie, PSL Research University, CNRS UMR144, F-75005 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5894-8978","authenticated-orcid":false,"given":"Vincent","family":"El Ghouzzi","sequence":"additional","affiliation":[{"name":"NeuroDiderot, Inserm, Universit\u00e9 Paris Cit\u00e9, F-75019 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1016\/j.tins.2020.07.009","article-title":"Basal Progenitor Morphology and Neocortex Evolution","volume":"43","author":"Kalebic","year":"2020","journal-title":"Trends Neurosci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.15252\/embj.201593701","article-title":"Cerebral cortex expansion and folding: What have we learned?","volume":"35","author":"Borrell","year":"2016","journal-title":"EMBO J."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"381","DOI":"10.3389\/fncel.2019.00381","article-title":"Genes and Mechanisms Involved in the Generation and Amplification of Basal Radial Glial Cells","volume":"13","author":"Penisson","year":"2019","journal-title":"Front. Cell. Neurosci."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Heide, M., and Huttner, W.B. (2021). Human-Specific Genes, Cortical Progenitor Cells, and Microcephaly. Cells, 10.","DOI":"10.3390\/cells10051209"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1038\/nrn2097","article-title":"Cell-cycle control and cortical development","volume":"8","author":"Dehay","year":"2007","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"772","DOI":"10.1016\/j.cub.2015.01.041","article-title":"Human-Chimpanzee Differences in a FZD8 Enhancer Alter Cell-Cycle Dynamics in the Developing Neocortex","volume":"25","author":"Boyd","year":"2015","journal-title":"Curr. Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1038\/nmeth.4576","article-title":"Organoids","volume":"15","year":"2018","journal-title":"Nat. Methods"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"982","DOI":"10.1016\/j.molmed.2018.09.005","article-title":"Brain Organoids and the Study of Neurodevelopment","volume":"24","author":"Trujillo","year":"2018","journal-title":"Trends Mol. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1038\/s41418-020-0566-4","article-title":"Brain organoids: An ensemble of bioassays to investigate human neurodevelopment and disease","volume":"28","author":"Sidhaye","year":"2021","journal-title":"Cell Death Differ."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e347","DOI":"10.1002\/wdev.347","article-title":"Using brain organoids to study human neurodevelopment, evolution and disease","volume":"9","author":"Kyrousi","year":"2020","journal-title":"Wiley Interdiscip. Rev. Dev. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"784700","DOI":"10.3389\/fcell.2021.784700","article-title":"Autosomal Recessive Primary Microcephaly: Not Just a Small Brain","volume":"9","author":"Zaqout","year":"2021","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Jalink, P., and Caiazzo, M. (2021). Brain Organoids: Filling the Need for a Human Model of Neurological Disorder. Biology, 10.","DOI":"10.3390\/biology10080740"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1038\/nn1402","article-title":"Directed differentiation of telencephalic precursors from embryonic stem cells","volume":"8","author":"Watanabe","year":"2005","journal-title":"Nat. Neurosci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1016\/j.stem.2008.09.002","article-title":"Self-Organized Formation of Polarized Cortical Tissues from ESCs and Its Active Manipulation by Extrinsic Signals","volume":"3","author":"Eiraku","year":"2008","journal-title":"Cell Stem Cell"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1038\/nature12517","article-title":"Cerebral organoids model human brain development and microcephaly","volume":"501","author":"Lancaster","year":"2013","journal-title":"Nature"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"15","DOI":"10.3389\/fnsyn.2018.00015","article-title":"Modeling Neurological Diseases With Human Brain Organoids","volume":"10","author":"Wang","year":"2018","journal-title":"Front. Synaptic Neurosci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1038\/nbt.3906","article-title":"Guided self-organization and cortical plate formation in human brain organoids","volume":"35","author":"Lancaster","year":"2017","journal-title":"Nat. Biotechnol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.conb.2020.09.006","article-title":"Modeling brain development and diseases with human cerebral organoids","volume":"66","author":"Shi","year":"2021","journal-title":"Curr. Opin. Neurobiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1038\/nbt.1529","article-title":"Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling","volume":"27","author":"Chambers","year":"2009","journal-title":"Nat. Biotechnol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1238","DOI":"10.1016\/j.cell.2016.04.032","article-title":"Brain-Region-Specific Organoids Using Mini-bioreactors for Modeling ZIKV Exposure","volume":"165","author":"Qian","year":"2016","journal-title":"Cell"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1038\/nmeth.3415","article-title":"Functional cortical neurons and astrocytes from human pluripotent stem cells in 3D culture","volume":"12","author":"Sloan","year":"2015","journal-title":"Nat. Methods"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1014","DOI":"10.1016\/j.neuron.2020.08.029","article-title":"Upgrading the Physiological Relevance of Human Brain Organoids","volume":"107","author":"Urenda","year":"2020","journal-title":"Neuron"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1038\/nprot.2017.152","article-title":"Generation of human brain region-specific organoids using a miniaturized spinning bioreactor","volume":"13","author":"Qian","year":"2018","journal-title":"Nat. Protoc."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"20284","DOI":"10.1073\/pnas.1315710110","article-title":"Self-organization of axial polarity, inside-out layer pattern, and species-specific progenitor dynamics in human ES cell-derived neocortex","volume":"110","author":"Kadoshima","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_25","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_26","doi-asserted-by":"crossref","first-page":"2062","DOI":"10.1038\/s41596-018-0032-7","article-title":"Generation and assembly of human brain region-specific three-dimensional cultures","volume":"13","author":"Sloan","year":"2018","journal-title":"Nat. Protoc."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1038\/nmeth.4304","article-title":"Fused cerebral organoids model interactions between brain regions","volume":"14","author":"Bagley","year":"2017","journal-title":"Nat. Methods"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1038\/nature22330","article-title":"Assembly of functionally integrated human forebrain spheroids","volume":"545","author":"Birey","year":"2017","journal-title":"Nature"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1016\/j.stem.2017.07.007","article-title":"Fusion of Regionally Specified hPSC-Derived Organoids Models Human Brain Development and Interneuron Migration","volume":"21","author":"Xiang","year":"2017","journal-title":"Cell Stem Cell"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1016\/j.devcel.2010.05.017","article-title":"CDK5RAP2 regulates centriole engagement and cohesion in mice","volume":"18","author":"Barrera","year":"2010","journal-title":"Dev. Cell"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1016\/j.neuron.2010.03.036","article-title":"Cdk5rap2 interacts with pericentrin to maintain the neural progenitor pool in the developing neocortex","volume":"66","author":"Buchman","year":"2010","journal-title":"Neuron"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1907","DOI":"10.1242\/dev.040410","article-title":"Cdk5rap2 regulates centrosome function and chromosome segregation in neuronal progenitors","volume":"137","author":"Lizarraga","year":"2010","journal-title":"Development"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"16595","DOI":"10.1073\/pnas.1010494107","article-title":"Mutations in mouse Aspm (abnormal spindle-like microcephaly associated) cause not only microcephaly but also major defects in the germline","volume":"107","author":"Pulvers","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1219","DOI":"10.1016\/j.neuron.2016.09.005","article-title":"Transformation of the Radial Glia Scaffold Demarcates Two Stages of Human Cerebral Cortex Development","volume":"91","author":"Nowakowski","year":"2016","journal-title":"Neuron"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1038\/nn.2807","article-title":"A new subtype of progenitor cell in the mouse embryonic neocortex","volume":"14","author":"Wang","year":"2011","journal-title":"Nat. Neurosci."},{"key":"ref_36","first-page":"dev169276","article-title":"A novel population of Hopx-dependent basal radial glial cells in the developing mouse neocortex","volume":"145","author":"Vaid","year":"2018","journal-title":"Dev. Camb. Engl."},{"key":"ref_37","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_38","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.celrep.2017.03.047","article-title":"An Organoid-Based Model of Cortical Development Identifies Non-Cell-Autonomous Defects in Wnt Signaling Contributing to Miller-Dieker Syndrome","volume":"19","author":"Iefremova","year":"2017","journal-title":"Cell Rep."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1016\/j.stem.2016.12.007","article-title":"Human iPSC-Derived Cerebral Organoids Model Cellular Features of Lissencephaly and Reveal Prolonged Mitosis of Outer Radial Glia","volume":"20","author":"Bershteyn","year":"2017","journal-title":"Cell Stem Cell"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1038\/nrm4062","article-title":"Centrosome function and assembly in animal cells","volume":"16","author":"Conduit","year":"2015","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1665","DOI":"10.1038\/ncomms2647","article-title":"Mitotic spindle orientation predicts outer radial glial cell generation in human neocortex","volume":"4","author":"LaMonica","year":"2013","journal-title":"Nat. Commun."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1038\/s41556-019-0436-9","article-title":"Endfoot regeneration restricts radial glial state and prevents translocation into the outer subventricular zone in early mammalian brain development","volume":"22","author":"Fujita","year":"2020","journal-title":"Nat. Cell Biol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1016\/j.tig.2009.09.011","article-title":"Primary microcephaly: Do all roads lead to Rome?","volume":"25","author":"Thornton","year":"2009","journal-title":"Trends Genet."},{"key":"ref_44","unstructured":"Adam, M.P., Ardinger, H.H., Pagon, R.A., Wallace, S.E., Bean, L.J., Gripp, K.W., Mirzaa, G.M., and Amemiya, A. (1993). ASPM Primary Microcephaly. GeneReviews\u00ae, University of Washington, Seattle."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1002\/humu.23381","article-title":"Autosomal recessive primary microcephaly due to ASPM mutations: An update","volume":"39","author":"Letard","year":"2018","journal-title":"Hum. Mutat."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1038\/s41586-018-0035-0","article-title":"Aspm knockout ferret reveals an evolutionary mechanism governing cerebral cortical size","volume":"556","author":"Johnson","year":"2018","journal-title":"Nature"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"661759","DOI":"10.3389\/fcell.2021.661759","article-title":"The Ferret as a Model System for Neocortex Development and Evolution","volume":"9","author":"Gilardi","year":"2021","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1007\/s13238-017-0479-2","article-title":"Recapitulating cortical development with organoid culture in vitro and modeling abnormal spindle-like (ASPM related primary) microcephaly disease","volume":"8","author":"Li","year":"2017","journal-title":"Protein Cell"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2329","DOI":"10.1038\/nprot.2014.158","article-title":"Generation of cerebral organoids from human pluripotent stem cells","volume":"9","author":"Lancaster","year":"2014","journal-title":"Nat. Protoc."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"803","DOI":"10.15252\/embj.201593679","article-title":"CPAP promotes timely cilium disassembly to maintain neural progenitor pool","volume":"35","author":"Gabriel","year":"2016","journal-title":"EMBO J."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1016\/j.stem.2009.05.026","article-title":"Cdk4\/cyclinD1 overexpression in neural stem cells shortens G1, delays neurogenesis, and promotes the generation and expansion of basal progenitors","volume":"5","author":"Lange","year":"2009","journal-title":"Cell Stem Cell"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"21924","DOI":"10.1073\/pnas.0909894106","article-title":"Forced G1-phase reduction alters mode of division, neuron number, and laminar phenotype in the cerebral cortex","volume":"106","author":"Pilaz","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2612","DOI":"10.1038\/s41467-019-10497-2","article-title":"Modeling microcephaly with cerebral organoids reveals a WDR62-CEP170-KIF2A pathway promoting cilium disassembly in neural progenitors","volume":"10","author":"Zhang","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"4038","DOI":"10.1038\/s41467-020-17454-4","article-title":"Loss of NARS1 impairs progenitor proliferation in cortical brain organoids and leads to microcephaly","volume":"11","author":"Wang","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"115","DOI":"10.3389\/fncel.2020.00115","article-title":"Human Brain Organoids to Decode Mechanisms of Microcephaly","volume":"14","author":"Gabriel","year":"2020","journal-title":"Front. Cell. Neurosci."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1016\/S0140-6736(16)00320-2","article-title":"Zika virus and microcephaly: Why is this situation a PHEIC?","volume":"387","author":"Heymann","year":"2016","journal-title":"Lancet"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1038\/nature18296","article-title":"The Brazilian Zika virus strain causes birth defects in experimental models","volume":"534","author":"Cugola","year":"2016","journal-title":"Nature"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1016\/j.stem.2016.04.014","article-title":"Zika Virus Depletes Neural Progenitors in Human Cerebral Organoids through Activation of the Innate Immune Receptor TLR3","volume":"19","author":"Dang","year":"2016","journal-title":"Cell Stem Cell"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1016\/j.stem.2016.12.005","article-title":"Recent Zika Virus Isolates Induce Premature Differentiation of Neural Progenitors in Human Brain Organoids","volume":"20","author":"Gabriel","year":"2017","journal-title":"Cell Stem Cell"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1016\/j.neuron.2007.10.001","article-title":"The Story of Rett Syndrome: From Clinic to Neurobiology","volume":"56","author":"Chahrour","year":"2007","journal-title":"Neuron"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"610427","DOI":"10.3389\/fcell.2020.610427","article-title":"Modeling Rett Syndrome With Human Patient-Specific Forebrain Organoids","volume":"8","author":"Gomes","year":"2020","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1016\/S1474-4422(15)00250-1","article-title":"The genetic landscape of the epileptic encephalopathies of infancy and childhood","volume":"15","author":"McTague","year":"2016","journal-title":"Lancet Neurol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1159\/000497035","article-title":"Golgipathies in Neurodevelopment: A New View of Old Defects","volume":"40","author":"Rasika","year":"2019","journal-title":"Dev. Neurosci."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"e13610","DOI":"10.15252\/emmm.202013610","article-title":"Modeling genetic epileptic encephalopathies using brain organoids","volume":"13","author":"Steinberg","year":"2021","journal-title":"EMBO Mol. Med."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.pneurobio.2017.03.007","article-title":"Golgi trafficking defects in postnatal microcephaly: The evidence for \u201cGolgipathies\u201d","volume":"153","author":"Passemard","year":"2017","journal-title":"Prog. Neurobiol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"3349","DOI":"10.1074\/jbc.M114.608174","article-title":"Cohen syndrome-associated protein COH1 physically and functionally interacts with the small GTPase RAB6 at the Golgi complex and directs neurite outgrowth","volume":"290","author":"Seifert","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1608","DOI":"10.1038\/s41467-019-09617-9","article-title":"SNAREs define targeting specificity of trafficking vesicles by combinatorial interaction with tethering factors","volume":"10","author":"Koike","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Lee, Y.-K., Hwang, S.-K., Lee, S.-K., Yang, J., Kwak, J.-H., Seo, H., Ahn, H., Lee, Y.-S., Kim, J., and Lim, C.-S. (2020). Cohen Syndrome Patient iPSC-Derived Neurospheres and Forebrain-Like Glutamatergic Neurons Reveal Reduced Proliferation of Neural Progenitor Cells and Altered Expression of Synapse Genes. J. Clin. Med., 9.","DOI":"10.3390\/jcm9061886"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1016\/j.cell.2007.11.019","article-title":"Induction of pluripotent stem cells from adult human fibroblasts by defined factors","volume":"131","author":"Takahashi","year":"2007","journal-title":"Cell"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1016\/j.stemcr.2018.06.012","article-title":"Recent Trends in Research with Human Pluripotent Stem Cells: Impact of Research and Use of Cell Lines in Experimental Research and Clinical Trials","volume":"11","author":"Guhr","year":"2018","journal-title":"Stem Cell Rep."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1038\/nature09342","article-title":"Epigenetic memory in induced pluripotent stem cells","volume":"467","author":"Kim","year":"2010","journal-title":"Nature"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.stem.2011.06.007","article-title":"Epigenetic memory and preferential lineage-specific differentiation in induced pluripotent stem cells derived from human pancreatic islet beta cells","volume":"9","author":"Russ","year":"2011","journal-title":"Cell Stem Cell"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1242\/dev.128389","article-title":"Metabolic remodeling during the loss and acquisition of pluripotency","volume":"144","author":"Mathieu","year":"2017","journal-title":"Development"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"107732","DOI":"10.1016\/j.celrep.2020.107732","article-title":"Variable Outcomes in Neural Differentiation of Human PSCs Arise from Intrinsic Differences in Developmental Signaling Pathways","volume":"31","author":"Strano","year":"2020","journal-title":"Cell Rep."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"2300","DOI":"10.1634\/stemcells.2008-0183","article-title":"Control of human embryonic stem cell colony and aggregate size heterogeneity influences differentiation trajectories","volume":"26","author":"Bauwens","year":"2008","journal-title":"Stem Cells"},{"key":"ref_76","first-page":"e56768","article-title":"Generation of Standardized and Reproducible Forebrain-type Cerebral Organoids from Human Induced Pluripotent Stem Cells","volume":"131","author":"Krefft","year":"2018","journal-title":"J. Vis. Exp. JoVE"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1038\/s41592-018-0255-0","article-title":"Reliability of human cortical organoid generation","volume":"16","author":"Yoon","year":"2019","journal-title":"Nat. Methods"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1007\/s00335-017-9684-9","article-title":"Editing the genome of hiPSC with CRISPR\/Cas9: Disease models","volume":"28","author":"Bassett","year":"2017","journal-title":"Mamm. Genome Off. J. Int. Mamm. Genome Soc."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1016\/j.ajhg.2016.07.004","article-title":"Biallelic Mutations in Citron Kinase Link Mitotic Cytokinesis to Human Primary Microcephaly","volume":"99","author":"Li","year":"2016","journal-title":"Am. J. Hum. Genet."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1038\/s10038-019-0574-8","article-title":"Verification and rectification of cell type-specific splicing of a Seckel syndrome-associated ATR mutation using iPS cell model","volume":"64","author":"Ichisima","year":"2019","journal-title":"J. Hum. Genet."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"eaaw0682","DOI":"10.1126\/scitranslmed.aaw0682","article-title":"Human neurons from Christianson syndrome iPSCs reveal mutation-specific responses to rescue strategies","volume":"13","author":"Lizarraga","year":"2021","journal-title":"Sci. Transl. Med."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1316","DOI":"10.15252\/embj.201694700","article-title":"Self-organized developmental patterning and differentiation in cerebral organoids","volume":"36","author":"Renner","year":"2017","journal-title":"EMBO J."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"104282","DOI":"10.1016\/j.ejmg.2021.104282","article-title":"Human neuropathology confirms projection neuron and interneuron defects and delayed oligodendrocyte production and maturation in FOXG1 syndrome","volume":"64","author":"Wilpert","year":"2021","journal-title":"Eur. J. Med. Genet."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1111\/epi.12914","article-title":"Novel mutations in ATP1A3 associated with catastrophic early life epilepsy, episodic prolonged apnea, and postnatal microcephaly","volume":"56","author":"Paciorkowski","year":"2015","journal-title":"Epilepsia"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"2771","DOI":"10.1093\/hmg\/ddv038","article-title":"Dymeclin deficiency causes postnatal microcephaly, hypomyelination and reticulum-to-Golgi trafficking defects in mice and humans","volume":"24","author":"Dupuis","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"4216","DOI":"10.1523\/JNEUROSCI.3441-12.2013","article-title":"Microglia regulate the number of neural precursor cells in the developing cerebral cortex","volume":"33","author":"Cunningham","year":"2013","journal-title":"J. Neurosci. Off. J. Soc. Neurosci."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"12540","DOI":"10.1038\/ncomms12540","article-title":"Microglia contact induces synapse formation in developing somatosensory cortex","volume":"7","author":"Miyamoto","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1456","DOI":"10.1126\/science.1202529","article-title":"Synaptic pruning by microglia is necessary for normal brain development","volume":"333","author":"Paolicelli","year":"2011","journal-title":"Science"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1016\/j.neuron.2012.03.026","article-title":"Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner","volume":"74","author":"Schafer","year":"2012","journal-title":"Neuron"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1038\/s41592-018-0081-4","article-title":"Induction of myelinating oligodendrocytes in human cortical spheroids","volume":"15","author":"Madhavan","year":"2018","journal-title":"Nat. Methods"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1038\/s41593-018-0316-9","article-title":"Differentiation and maturation of oligodendrocytes in human three-dimensional neural cultures","volume":"22","author":"Marton","year":"2019","journal-title":"Nat. Neurosci."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"4167","DOI":"10.1038\/s41467-018-06684-2","article-title":"Microglia innately develop within cerebral organoids","volume":"9","author":"Ormel","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1016\/j.neuron.2017.03.042","article-title":"iPSC-Derived Human Microglia-like Cells to Study Neurological Diseases","volume":"94","author":"Abud","year":"2017","journal-title":"Neuron"},{"key":"ref_94","doi-asserted-by":"crossref","unstructured":"Fagerlund, I., Dougalis, A., Shakirzyanova, A., Gomez-Budia, M., Konttinen, H., Ohtonen, S., Fazaludeen, F., Koskuvi, M., Kuusisto, J., and Hernandez, D. (2021). Microglia Orchestrate Neuronal Activity in Brain Organoids. SSRN Electron. J.","DOI":"10.2139\/ssrn.3773789"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"dev166074","DOI":"10.1242\/dev.166074","article-title":"Brain organoids: Advances, applications and challenges","volume":"146","author":"Qian","year":"2019","journal-title":"Development"},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Shi, Y., Sun, L., Wang, M., Liu, J., Zhong, S., Li, R., Li, P., Guo, L., Fang, A., and Chen, R. (2020). Vascularized human cortical organoids (vOrganoids) model cortical development in vivo. PLoS Biol., 18.","DOI":"10.1371\/journal.pbio.3000705"},{"key":"ref_97","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_98","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1038\/s41593-019-0350-2","article-title":"Cerebral organoids at the air-liquid interface generate diverse nerve tracts with functional output","volume":"22","author":"Giandomenico","year":"2019","journal-title":"Nat. Neurosci."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1038\/s41596-020-00433-w","article-title":"Generation and long-term culture of advanced cerebral organoids for studying later stages of neural development","volume":"16","author":"Giandomenico","year":"2021","journal-title":"Nat. Protoc."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1016\/j.cell.2019.01.017","article-title":"Establishing Cerebral Organoids as Models of Human-Specific Brain Evolution","volume":"176","author":"Pollen","year":"2019","journal-title":"Cell"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1038\/s41593-021-00802-y","article-title":"Long-term maturation of human cortical organoids matches key early postnatal transitions","volume":"24","author":"Gordon","year":"2021","journal-title":"Nat. Neurosci."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1038\/s41586-020-1962-0","article-title":"Cell stress in cortical organoids impairs molecular subtype specification","volume":"578","author":"Bhaduri","year":"2020","journal-title":"Nature"},{"key":"ref_103","doi-asserted-by":"crossref","unstructured":"Garcia-Solaesa, V., Serrano-Lorenzo, P., Ramos-Arroyo, M.A., Bl\u00e1zquez, A., Pagola-Lorz, I., Artigas-L\u00f3pez, M., Arenas, J., Mart\u00edn, M.A., and Jeric\u00f3-Pascual, I. (2019). A Novel Missense Variant Associated with A Splicing Defect in A Myopathic Form of PGK1 Deficiency in The Spanish Population. Genes, 10.","DOI":"10.3390\/genes10100785"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1016\/j.ajhg.2016.06.011","article-title":"ARCN1 Mutations Cause a Recognizable Craniofacial Syndrome Due to COPI-Mediated Transport Defects","volume":"99","author":"Izumi","year":"2016","journal-title":"Am. J. Hum. Genet."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"369","DOI":"10.15698\/cst2019.12.206","article-title":"Endoplasmic reticulum and Golgi stress in microcephaly","volume":"3","author":"Passemard","year":"2019","journal-title":"Cell Stress"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"4730","DOI":"10.1038\/s41467-021-24775-5","article-title":"Microfluidic device with brain extracellular matrix promotes structural and functional maturation of human brain organoids","volume":"12","author":"Cho","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"3172","DOI":"10.1039\/C8LC00206A","article-title":"Millifluidic culture improves human midbrain organoid vitality and differentiation","volume":"18","author":"Berger","year":"2018","journal-title":"Lab. Chip"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/14\/2135\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:43:45Z","timestamp":1760139825000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/14\/2135"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,7]]},"references-count":107,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2022,7]]}},"alternative-id":["cells11142135"],"URL":"https:\/\/doi.org\/10.3390\/cells11142135","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,7]]}}}