{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T19:14:42Z","timestamp":1773342882882,"version":"3.50.1"},"reference-count":103,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,1,15]],"date-time":"2025-01-15T00:00:00Z","timestamp":1736899200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurosci."],"abstract":"<jats:p>Malformations of cortical development encompass a broad range of disorders associated with abnormalities in corticogenesis. Widespread abnormalities in neuronal formation or migration can lead to small head size or microcephaly with disorganized placement of cell types. Specific, localized malformations are termed focal cortical dysplasias (FCD). Neurodevelopmental disorders are common in all types of malformations of cortical development with the most prominent being refractory epilepsy, behavioral disorders such as autism spectrum disorder (ASD), and learning disorders. Several genetic pathways have been associated with these disorders from control of cell cycle and cytoskeletal dynamics in global malformations to variants in growth factor signaling pathways, especially those interacting with the mechanistic target of rapamycin (mTOR), in FCDs. Despite advances in understanding these disorders, the underlying developmental pathways that lead to lesion formation and mechanisms through which defects in cortical development cause specific neurological symptoms often remains unclear. One limitation is the difficulty in modeling these disorders, as animal models frequently do not faithfully mirror the human phenotype. To circumvent this obstacle, many investigators have turned to three-dimensional human stem cell models of the brain, known as organoids, because they recapitulate early neurodevelopmental processes. High throughput analysis of these organoids presents a promising opportunity to model pathophysiological processes across the breadth of malformations of cortical development. In this review, we highlight advances in understanding the pathophysiology of brain malformations using organoid models.<\/jats:p>","DOI":"10.3389\/fnins.2024.1522652","type":"journal-article","created":{"date-parts":[[2025,1,15]],"date-time":"2025-01-15T06:11:52Z","timestamp":1736921512000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Using cortical organoids to understand the pathogenesis of malformations of cortical development"],"prefix":"10.3389","volume":"18","author":[{"given":"Kellen D.","family":"Winden","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Isabel","family":"Gisser","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mustafa","family":"Sahin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,1,15]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"fcad222","DOI":"10.1093\/braincomms\/fcad222","article-title":"Lunapark deficiency leads to an autosomal recessive neurodevelopmental phenotype with a degenerative course, epilepsy and distinct brain anomalies","volume":"5","author":"Accogli","year":"2023","journal-title":"Brain Commun."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"830432","DOI":"10.3389\/fcell.2022.830432","article-title":"Modeling human primary microcephaly with hiPSC-derived brain organoids carrying CPAP-E1235V disease-associated mutant protein","volume":"10","author":"An","year":"2022","journal-title":"Front. Cell Dev. Biol."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"1382","DOI":"10.1016\/j.stem.2023.08.009","article-title":"LIF signaling regulates outer radial glial to interneuron fate during human cortical development","volume":"30","author":"Andrews","year":"2023","journal-title":"Cell Stem Cell"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"e58737","DOI":"10.7554\/eLife.58737","article-title":"mTOR signaling regulates the morphology and migration of outer radial glia in developing human cortex","volume":"9","author":"Andrews","year":"2020","journal-title":"eLife"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"1348","DOI":"10.1093\/brain\/aws019","article-title":"A developmental and genetic classification for malformations of cortical development: update 2012","volume":"135","author":"Barkovich","year":"2012","journal-title":"Brain"},{"key":"ref6","doi-asserted-by":"publisher","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":"ref7","doi-asserted-by":"publisher","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":"ref8","doi-asserted-by":"publisher","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":"ref9","doi-asserted-by":"publisher","first-page":"1568","DOI":"10.1038\/s41591-018-0139-y","article-title":"Genetically engineered human cortical spheroid models of tuberous sclerosis","volume":"24","author":"Blair","year":"2018","journal-title":"Nat. Med."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"577","DOI":"10.1111\/j.1440-1789.2008.00920.x","article-title":"Clinicopathological and immunohistochemical findings in an autopsy case of tuberous sclerosis complex","volume":"28","author":"Boer","year":"2008","journal-title":"Neuropathology"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"422","DOI":"10.1126\/science.1209037","article-title":"The centrosome in cells and organisms","volume":"335","author":"Bornens","year":"2012","journal-title":"Science"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"6429","DOI":"10.1073\/pnas.101122598","article-title":"Targeted mutagenesis of Lis1 disrupts cortical development and LIS1 homodimerization","volume":"98","author":"Cahana","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"15672","DOI":"10.1073\/pnas.1520760112","article-title":"Human cerebral organoids recapitulate gene expression programs of fetal neocortex development","volume":"112","author":"Camp","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"881","DOI":"10.1038\/s41586-023-06984-8","article-title":"An epigenetic barrier sets the timing of human neuronal maturation","volume":"626","author":"Ciceri","year":"2024","journal-title":"Nature"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"322","DOI":"10.1093\/cercor\/bht222","article-title":"ARX regulates cortical intermediate progenitor cell expansion and upper layer neuron formation through repression of Cdkn1c","volume":"25","author":"Colasante","year":"2015","journal-title":"Cereb. Cortex"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"1716","DOI":"10.1212\/WNL.0b013e3181e04325","article-title":"Biallelic TSC gene inactivation in tuberous sclerosis complex","volume":"74","author":"Crino","year":"2010","journal-title":"Neurology"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"696","DOI":"10.1002\/dneu.22816","article-title":"STRADA-mutant human cortical organoids model megalencephaly and exhibit delayed neuronal differentiation","volume":"81","author":"Dang","year":"2021","journal-title":"Dev. Neurobiol."},{"key":"ref18","doi-asserted-by":"publisher","first-page":"49","DOI":"10.3390\/cells9010049","article-title":"The mitotic apparatus and kinetochores in microcephaly and neurodevelopmental diseases","volume":"9","author":"Degrassi","year":"2019","journal-title":"Cells"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"e81716","DOI":"10.7554\/eLife.81716","article-title":"Microcephaly-associated protein WDR62 shuttles from the Golgi apparatus to the spindle poles in human neural progenitors","volume":"12","author":"Dell'Amico","year":"2023","journal-title":"Elife"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"797","DOI":"10.1002\/ana.24793","article-title":"Malformations of cortical development","volume":"80","author":"Desikan","year":"2016","journal-title":"Ann. Neurol."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"114173","DOI":"10.1016\/j.celrep.2024.114173","article-title":"Synergistic hyperactivation of both mTORC1 and mTORC2 underlies the neural abnormalities of PTEN-deficient human neurons and cortical organoids","volume":"43","author":"Dhaliwal","year":"2024","journal-title":"Cell Rep."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"573","DOI":"10.1038\/nrn.2017.107","article-title":"The use of brain organoids to investigate neural development and disease","volume":"18","author":"Di Lullo","year":"2017","journal-title":"Nat. Rev. Neurosci."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"eabf5546","DOI":"10.1126\/science.abf5546","article-title":"Amplification of human interneuron progenitors promotes brain tumors and neurological defects","volume":"375","author":"Eichmuller","year":"2022","journal-title":"Science"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"783","DOI":"10.1016\/j.neuron.2018.10.033","article-title":"Best practices for translational disease modeling using human iPSC-derived neurons","volume":"100","author":"Engle","year":"2018","journal-title":"Neuron"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"935","DOI":"10.1126\/science.abb5390","article-title":"A human tissue screen identifies a regulator of ER secretion as a brain-size determinant","volume":"370","author":"Esk","year":"2020","journal-title":"Science"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1093\/brain\/awac244","article-title":"Cerebral organoids containing an AUTS2 missense variant model microcephaly","volume":"146","author":"Fair","year":"2023","journal-title":"Brain"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"799","DOI":"10.1093\/hmg\/ddr511","article-title":"Postnatal neurogenesis generates heterotopias, olfactory micronodules and cortical infiltration following single-cell Tsc1 deletion","volume":"21","author":"Feliciano","year":"2012","journal-title":"Hum. Mol. Genet."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1007\/s00401-010-0768-9","article-title":"Role of cytoskeletal abnormalities in the neuropathology and pathophysiology of type I lissencephaly","volume":"121","author":"Friocourt","year":"2011","journal-title":"Acta Neuropathol."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"661","DOI":"10.1016\/j.braindev.2013.10.006","article-title":"Disruption of Aspm causes microcephaly with abnormal neuronal differentiation","volume":"36","author":"Fujimori","year":"2014","journal-title":"Brain and Development"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"19522","DOI":"10.1038\/s41598-024-69912-4","article-title":"AUTS2 disruption causes neuronal differentiation defects in human cerebral organoids through hyperactivation of the WNT\/beta-catenin pathway","volume":"14","author":"Geng","year":"2024","journal-title":"Sci. Rep."},{"key":"ref31","doi-asserted-by":"publisher","first-page":"1351","DOI":"10.1016\/j.stemcr.2024.07.008","article-title":"Cross-site reproducibility of human cortical organoids reveals consistent cell type composition and architecture","volume":"19","author":"Glass","year":"2024","journal-title":"Stem Cell Rep."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"e2112040119","DOI":"10.1073\/pnas.2112040119","article-title":"FASN-dependent de novo lipogenesis is required for brain development","volume":"119","author":"Gonzalez-Bohorquez","year":"2022","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref33","doi-asserted-by":"publisher","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":"ref34","doi-asserted-by":"publisher","first-page":"1515","DOI":"10.1038\/s41587-023-02031-z","article-title":"Combined small-molecule treatment accelerates maturation of human pluripotent stem cell-derived neurons","volume":"42","author":"Hergenreder","year":"2024","journal-title":"Nat. Biotechnol."},{"key":"ref35","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1038\/1221","article-title":"Graded reduction of Pafah1b1 (Lis1) activity results in neuronal migration defects and early embryonic lethality","volume":"19","author":"Hirotsune","year":"1998","journal-title":"Nat. Genet."},{"key":"ref36","doi-asserted-by":"publisher","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":"ref37","doi-asserted-by":"publisher","first-page":"eabn4705","DOI":"10.1126\/science.abn4705","article-title":"Mitochondria metabolism sets the species-specific tempo of neuronal development","volume":"379","author":"Iwata","year":"2023","journal-title":"Science"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1146\/annurev-genom-083117-021441","article-title":"The genetics of primary microcephaly","volume":"19","author":"Jayaraman","year":"2018","journal-title":"Annu. Rev. Genomics Hum. Genet."},{"key":"ref39","doi-asserted-by":"publisher","first-page":"813","DOI":"10.1016\/j.neuron.2016.09.056","article-title":"Microcephaly proteins Wdr62 and Aspm define a mother centriole complex regulating centriole biogenesis, apical complex, and cell fate","volume":"92","author":"Jayaraman","year":"2016","journal-title":"Neuron"},{"key":"ref40","doi-asserted-by":"publisher","first-page":"39902","DOI":"10.1038\/srep39902","article-title":"Katanin p80, NuMA and cytoplasmic dynein cooperate to control microtubule dynamics","volume":"7","author":"Jin","year":"2017","journal-title":"Sci. Rep."},{"key":"ref41","doi-asserted-by":"publisher","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":"ref42","doi-asserted-by":"publisher","first-page":"1767","DOI":"10.1038\/s41380-023-02325-3","article-title":"Germline PTEN genotype-dependent phenotypic divergence during the early neural developmental process of forebrain organoids","volume":"29","author":"Kang","year":"2024","journal-title":"Mol. Psychiatry"},{"key":"ref43","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1002\/humu.10310","article-title":"Mutations of ARX are associated with striking pleiotropy and consistent genotype-phenotype correlation","volume":"23","author":"Kato","year":"2004","journal-title":"Hum. Mutat."},{"key":"ref44","doi-asserted-by":"publisher","first-page":"R89","DOI":"10.1093\/hmg\/ddg086","article-title":"Lissencephaly and the molecular basis of neuronal migration","author":"Kato","year":"2003","journal-title":"Hum. Mol. Genet."},{"key":"ref45","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2012\/279834","article-title":"Synaptic plasticity and learning in animal models of tuberous sclerosis complex","volume":"2012","author":"Kirschstein","year":"2012","journal-title":"Neural Plast."},{"key":"ref46","doi-asserted-by":"publisher","first-page":"561","DOI":"10.1038\/s41591-019-0371-0","article-title":"Altered neuronal migratory trajectories in human cerebral organoids derived from individuals with neuronal heterotopia","volume":"25","author":"Klaus","year":"2019","journal-title":"Nat. Med."},{"key":"ref47","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1016\/j.neuron.2006.03.023","article-title":"Pten regulates neuronal arborization and social interaction in mice","volume":"50","author":"Kwon","year":"2006","journal-title":"Neuron"},{"key":"ref48","doi-asserted-by":"publisher","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":"ref49","doi-asserted-by":"publisher","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":"ref50","doi-asserted-by":"publisher","first-page":"972","DOI":"10.1016\/j.neuron.2019.10.002","article-title":"Xenotransplanted human cortical neurons reveal species-specific development and functional integration into mouse visual circuits","volume":"104","author":"Linaro","year":"2019","journal-title":"Neuron"},{"key":"ref51","doi-asserted-by":"publisher","first-page":"420","DOI":"10.1002\/ana.20949","article-title":"Activation of mammalian target of rapamycin in cytomegalic neurons of human cortical dysplasia","volume":"60","author":"Ljungberg","year":"2006","journal-title":"Ann. Neurol."},{"key":"ref52","doi-asserted-by":"publisher","first-page":"e247268","DOI":"10.1136\/bcr-2021-247268","article-title":"Phenotypic manifestations in FLNA-related periventricular nodular heterotopia: a case report and review of the literature","volume":"15","author":"Loft Nagel","year":"2022","journal-title":"BMJ Case Rep."},{"key":"ref53","doi-asserted-by":"publisher","first-page":"264","DOI":"10.1038\/nature13973","article-title":"Radial glia require PDGFD-PDGFRbeta signalling in human but not mouse neocortex","volume":"515","author":"Lui","year":"2014","journal-title":"Nature"},{"key":"ref54","doi-asserted-by":"publisher","first-page":"3369","DOI":"10.1016\/j.celrep.2016.12.001","article-title":"Cerebral organoids recapitulate Epigenomic signatures of the human fetal brain","volume":"17","author":"Luo","year":"2016","journal-title":"Cell Rep."},{"key":"ref55","doi-asserted-by":"publisher","first-page":"5546","DOI":"10.1523\/JNEUROSCI.5540-06.2007","article-title":"A mouse model of tuberous sclerosis: neuronal loss of Tsc1 causes dysplastic and ectopic neurons, reduced myelination, seizure activity, and limited survival","volume":"27","author":"Meikle","year":"2007","journal-title":"J. Neurosci."},{"key":"ref56","doi-asserted-by":"publisher","first-page":"359","DOI":"10.1038\/s41586-023-06564-w","article-title":"Assembloid CRISPR screens reveal impact of disease genes in human neurodevelopment","volume":"622","author":"Meng","year":"2023","journal-title":"Nature"},{"key":"ref57","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1002\/wdev.67","article-title":"Cytoskeleton in action: lissencephaly, a neuronal migration disorder","volume":"2","author":"Moon","year":"2013","journal-title":"Wiley Interdiscip. Rev. Dev. Biol."},{"key":"ref58","doi-asserted-by":"publisher","first-page":"537","DOI":"10.1016\/j.celrep.2014.12.051","article-title":"Self-organization of polarized cerebellar tissue in 3D culture of human pluripotent stem cells","volume":"10","author":"Muguruma","year":"2015","journal-title":"Cell Rep."},{"key":"ref59","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1186\/s11689-016-9142-0","article-title":"Specific pattern of maturation and differentiation in the formation of cortical tubers in tuberous sclerosis omplex (TSC): evidence from layer-specific marker expression","volume":"8","author":"Muhlebner","year":"2016","journal-title":"J. Neurodev. Disord."},{"key":"ref60","doi-asserted-by":"publisher","first-page":"1899","DOI":"10.1111\/epi.17301","article-title":"The ILAE consensus classification of focal cortical dysplasia: An update proposed by an ad hoc task force of the ILAE diagnostic methods commission","volume":"63","author":"Najm","year":"2022","journal-title":"Epilepsia"},{"key":"ref61","doi-asserted-by":"publisher","first-page":"3949","DOI":"10.1093\/brain\/awae185","article-title":"Biallelic null variants in PNPLA8 cause microcephaly by reducing the number of basal radial glia","volume":"147","author":"Nakamura","year":"2024","journal-title":"Brain"},{"key":"ref62","doi-asserted-by":"publisher","first-page":"303","DOI":"10.3389\/fcell.2019.00303","article-title":"Human cerebral organoids and fetal brain tissue share proteomic similarities","volume":"7","author":"Nascimento","year":"2019","journal-title":"Front. Cell Dev. Biol."},{"key":"ref63","doi-asserted-by":"publisher","first-page":"1989","DOI":"10.1073\/pnas.0804428106","article-title":"Haploinsufficiency for Pten and serotonin transporter cooperatively influences brain size and social behavior","volume":"106","author":"Page","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref64","doi-asserted-by":"publisher","first-page":"e175435","DOI":"10.1172\/JCI175435","article-title":"Modeling primary microcephaly with human brain organoids reveals fundamental roles of CIT kinase activity","volume":"134","author":"Pallavicini","year":"2024","journal-title":"J. Clin. Invest."},{"key":"ref65","doi-asserted-by":"publisher","first-page":"437","DOI":"10.1038\/nature25032","article-title":"The rise of three-dimensional human brain cultures","volume":"553","author":"Pasca","year":"2018","journal-title":"Nature"},{"key":"ref66","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1126\/science.aau5729","article-title":"Assembling human brain organoids","volume":"363","author":"Pasca","year":"2019","journal-title":"Science"},{"key":"ref67","doi-asserted-by":"publisher","first-page":"907","DOI":"10.1038\/s41586-022-05219-6","article-title":"A nomenclature consensus for nervous system organoids and assembloids","volume":"609","author":"Pasca","year":"2022","journal-title":"Nature"},{"key":"ref68","doi-asserted-by":"publisher","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":"Pasca","year":"2015","journal-title":"Nat. Methods"},{"key":"ref69","doi-asserted-by":"publisher","first-page":"1536","DOI":"10.1212\/WNL.0000000000002055","article-title":"Tubers are neither static nor discrete: evidence from serial diffusion tensor imaging","volume":"85","author":"Peters","year":"2015","journal-title":"Neurology"},{"key":"ref70","doi-asserted-by":"publisher","first-page":"2773","DOI":"10.1093\/hmg\/ddad107","article-title":"Cell-type specific defects in PTEN-mutant cortical organoids converge on abnormal circuit activity","volume":"32","author":"Pigoni","year":"2023","journal-title":"Hum. Mol. Genet."},{"key":"ref71","doi-asserted-by":"publisher","first-page":"1607","DOI":"10.1093\/jnci\/djt277","article-title":"Cowden syndrome and the PTEN hamartoma tumor syndrome: systematic review and revised diagnostic criteria","volume":"105","author":"Pilarski","year":"2013","journal-title":"J. Natl. Cancer Inst."},{"key":"ref72","doi-asserted-by":"publisher","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":"ref73","doi-asserted-by":"publisher","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":"ref74","doi-asserted-by":"publisher","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":"ref75","doi-asserted-by":"publisher","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":"ref76","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1038\/s41586-022-05277-w","article-title":"Maturation and circuit integration of transplanted human cortical organoids","volume":"610","author":"Revah","year":"2022","journal-title":"Nature"},{"key":"ref77","doi-asserted-by":"publisher","first-page":"1265","DOI":"10.1038\/s41587-020-0525-0","article-title":"Modeling neural tube development by differentiation of human embryonic stem cells in a microfluidic WNT gradient","volume":"38","author":"Rifes","year":"2020","journal-title":"Nat. Biotechnol."},{"key":"ref78","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1016\/j.semcdb.2017.09.031","article-title":"Genetics and mechanisms leading to human cortical malformations","volume":"76","author":"Romero","year":"2018","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref79","doi-asserted-by":"publisher","first-page":"584","DOI":"10.1016\/j.stem.2009.11.009","article-title":"Technical challenges in using human induced pluripotent stem cells to model disease","volume":"5","author":"Saha","year":"2009","journal-title":"Cell Stem Cell"},{"key":"ref80","doi-asserted-by":"publisher","first-page":"8896","DOI":"10.1038\/ncomms9896","article-title":"Generation of functional hippocampal neurons from self-organizing human embryonic stem cell-derived dorsomedial telencephalic tissue","volume":"6","author":"Sakaguchi","year":"2015","journal-title":"Nat. Commun."},{"key":"ref81","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1146\/annurev-genom-083118-015354","article-title":"Genetic etiologies, diagnosis, and treatment of tuberous sclerosis complex","volume":"20","author":"Salussolia","year":"2019","journal-title":"Annu. Rev. Genomics Hum. Genet."},{"key":"ref82","doi-asserted-by":"publisher","first-page":"796","DOI":"10.1016\/j.stemcr.2024.04.008","article-title":"Rigor and reproducibility in human brain organoid research: where we are and where we need to go","volume":"19","author":"Sandoval","year":"2024","journal-title":"Stem Cell Rep."},{"key":"ref83","doi-asserted-by":"publisher","first-page":"154","DOI":"10.1016\/j.pediatrneurol.2023.06.015","article-title":"Variants in PTEN are associated with a diverse Spectrum of cortical dysplasia","volume":"147","author":"Shelkowitz","year":"2023","journal-title":"Pediatr. Neurol."},{"key":"ref84","doi-asserted-by":"publisher","first-page":"1117","DOI":"10.1002\/ajmg.a.61532","article-title":"Brain morphological analysis in PTEN hamartoma tumor syndrome","volume":"182","author":"Shiohama","year":"2020","journal-title":"Am. J. Med. Genet. A"},{"key":"ref85","doi-asserted-by":"publisher","first-page":"36559","DOI":"10.1038\/srep36559","article-title":"Superimposing status epilepticus on neuron subset-specific PTEN Haploinsufficient and wild type mice results in long-term changes in behavior","volume":"6","author":"Smith","year":"2016","journal-title":"Sci. Rep."},{"key":"ref86","doi-asserted-by":"publisher","first-page":"615","DOI":"10.1016\/j.cell.2018.09.010","article-title":"Stem cells, genome editing, and the path to translational medicine","volume":"175","author":"Soldner","year":"2018","journal-title":"Cell"},{"key":"ref87","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1016\/j.neuroscience.2016.11.017","article-title":"Molecular neurobiology of mTOR","volume":"341","author":"Switon","year":"2017","journal-title":"Neuroscience"},{"key":"ref88","doi-asserted-by":"publisher","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":"ref89","doi-asserted-by":"publisher","first-page":"970","DOI":"10.1038\/nn1934","article-title":"Dual subcellular roles for LIS1 and dynein in radial neuronal migration in live brain tissue","volume":"10","author":"Tsai","year":"2007","journal-title":"Nat. Neurosci."},{"key":"ref90","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1002\/ana.10283","article-title":"Astrocyte-specific TSC1 conditional knockout mice exhibit abnormal neuronal organization and seizures","volume":"52","author":"Uhlmann","year":"2002","journal-title":"Ann. Neurol."},{"key":"ref91","doi-asserted-by":"publisher","first-page":"3770","DOI":"10.1016\/j.cell.2022.09.010","article-title":"Proper acquisition of cell class identity in organoids allows definition of fate specification programs of the human cerebral cortex","volume":"185","author":"Uzquiano","year":"2022","journal-title":"Cell"},{"key":"ref92","doi-asserted-by":"publisher","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":"ref93","doi-asserted-by":"publisher","first-page":"114031","DOI":"10.1016\/j.celrep.2024.114031","article-title":"Generation of human cerebral organoids with a structured outer subventricular zone","volume":"43","author":"Walsh","year":"2024","journal-title":"Cell Rep."},{"key":"ref94","doi-asserted-by":"publisher","first-page":"e2209983120","DOI":"10.1073\/pnas.2209983120","article-title":"TMEM161B modulates radial glial scaffolding in neocortical development","volume":"120","author":"Wang","year":"2023","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref95","doi-asserted-by":"publisher","first-page":"2220","DOI":"10.1016\/j.stemcr.2022.08.013","article-title":"TGFbeta superfamily signaling regulates the state of human stem cell pluripotency and capacity to create well-structured telencephalic organoids","volume":"17","author":"Watanabe","year":"2022","journal-title":"Stem Cell Rep."},{"key":"ref96","doi-asserted-by":"publisher","first-page":"517","DOI":"10.1016\/j.celrep.2017.09.047","article-title":"Self-organized cerebral organoids with human-specific features predict effective drugs to combat Zika virus infection","volume":"21","author":"Watanabe","year":"2017","journal-title":"Cell Rep."},{"key":"ref97","doi-asserted-by":"publisher","first-page":"1252","DOI":"10.1093\/hmg\/ddp025","article-title":"Loss of Tsc2 in radial glia models the brain pathology of tuberous sclerosis complex in the mouse","volume":"18","author":"Way","year":"2009","journal-title":"Hum. Mol. Genet."},{"key":"ref98","doi-asserted-by":"publisher","first-page":"379","DOI":"10.1038\/s41419-024-06768-6","article-title":"Biallelic variants in CSMD1 are implicated in a neurodevelopmental disorder with intellectual disability and variable cortical malformations","volume":"15","author":"Werren","year":"2024","journal-title":"Cell Death Dis."},{"key":"ref99","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1146\/annurev-neuro-080317-061747","article-title":"Abnormal mTOR activation in autism","volume":"41","author":"Winden","year":"2018","journal-title":"Annu. Rev. Neurosci."},{"key":"ref100","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1055\/s-0035-1552622","article-title":"Megalencephaly and macrocephaly","volume":"35","author":"Winden","year":"2015","journal-title":"Semin. Neurol."},{"key":"ref101","doi-asserted-by":"publisher","first-page":"391","DOI":"10.1038\/s41586-024-07204-7","article-title":"A patterned human neural tube model using microfluidic gradients","volume":"628","author":"Xue","year":"2024","journal-title":"Nature"},{"key":"ref102","doi-asserted-by":"publisher","first-page":"4286","DOI":"10.1093\/hmg\/dds262","article-title":"Graded loss of tuberin in an allelic series of brain models of TSC correlates with survival, and biochemical, histological and behavioral features","volume":"21","author":"Yuan","year":"2012","journal-title":"Hum. Mol. Genet."},{"key":"ref103","doi-asserted-by":"publisher","first-page":"1376","DOI":"10.1038\/s41593-024-01652-0","article-title":"Single-cell epigenomic reconstruction of developmental trajectories from pluripotency in human neural organoid systems","volume":"27","author":"Zenk","year":"2024","journal-title":"Nat. Neurosci."}],"container-title":["Frontiers in Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnins.2024.1522652\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,1,15]],"date-time":"2025-01-15T06:11:56Z","timestamp":1736921516000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnins.2024.1522652\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,15]]},"references-count":103,"alternative-id":["10.3389\/fnins.2024.1522652"],"URL":"https:\/\/doi.org\/10.3389\/fnins.2024.1522652","relation":{},"ISSN":["1662-453X"],"issn-type":[{"value":"1662-453X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,15]]},"article-number":"1522652"}}