{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,2]],"date-time":"2026-11-02T22:10:30Z","timestamp":1793657430044,"version":"4.5.1"},"reference-count":82,"publisher":"Springer Science and Business Media LLC","issue":"10","license":[{"start":{"date-parts":[[2021,8,19]],"date-time":"2021-08-19T00:00:00Z","timestamp":1629331200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.springer.com\/tdm"},{"start":{"date-parts":[[2021,8,19]],"date-time":"2021-08-19T00:00:00Z","timestamp":1629331200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.springer.com\/tdm"}],"funder":[{"DOI":"10.13039\/100000065","name":"U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["NS091859"],"award-info":[{"award-number":["NS091859"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["NS051630"],"award-info":[{"award-number":["NS051630"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["NS111602"],"award-info":[{"award-number":["NS111602"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009633","name":"U.S. Department of Health & Human Services | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development","doi-asserted-by":"publisher","award":["HD104458"],"award-info":[{"award-number":["HD104458"]}],"id":[{"id":"10.13039\/100009633","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005713","name":"United States Department of Defense | Office of the Secretary of Defense","doi-asserted-by":"publisher","award":["W81XWH1910068"],"award-info":[{"award-number":["W81XWH1910068"]}],"id":[{"id":"10.13039\/100005713","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000025","name":"U.S. Department of Health & Human Services | NIH | National Institute of Mental Health","doi-asserted-by":"publisher","award":["MH123711"],"award-info":[{"award-number":["MH123711"]}],"id":[{"id":"10.13039\/100000025","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000025","name":"U.S. Department of Health & Human Services | NIH | National Institute of Mental Health","doi-asserted-by":"publisher","award":["MH121102"],"award-info":[{"award-number":["MH121102"]}],"id":[{"id":"10.13039\/100000025","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Neurosci"],"published-print":{"date-parts":[[2021,10]]},"DOI":"10.1038\/s41593-021-00913-6","type":"journal-article","created":{"date-parts":[[2021,8,19]],"date-time":"2021-08-19T12:10:21Z","timestamp":1629375021000},"page":"1377-1391","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":180,"title":["A human forebrain organoid model of fragile X syndrome exhibits altered neurogenesis and highlights new treatment strategies"],"prefix":"10.1038","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5622-4570","authenticated-orcid":false,"given":"Yunhee","family":"Kang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yujing","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanfei","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weibo","family":"Niu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8359-0533","authenticated-orcid":false,"given":"Ziyi","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiying","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ranhui","family":"Duan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1219-061X","authenticated-orcid":false,"given":"Tianmin","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5980-5001","authenticated-orcid":false,"given":"Nisha","family":"Raj","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6222-6177","authenticated-orcid":false,"given":"Feiran","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Dou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chongchong","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2622-0127","authenticated-orcid":false,"given":"Gary J.","family":"Bassell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen T.","family":"Warren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily G.","family":"Allen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6137-6659","authenticated-orcid":false,"given":"Peng","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1518-3845","authenticated-orcid":false,"given":"Zhexing","family":"Wen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,8,19]]},"reference":[{"key":"913_CR1","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1146\/annurev-pathol-011811-132457","volume":"7","author":"MR Santoro","year":"2012","unstructured":"Santoro, M. R., Bray, S. M. & Warren, S. T. Molecular mechanisms of fragile X syndrome: a twenty-year perspective. Annu. Rev. Pathol. 7, 219\u2013245 (2012).","journal-title":"Annu. Rev. Pathol."},{"key":"913_CR2","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1038\/nrn4001","volume":"16","author":"JD Richter","year":"2015","unstructured":"Richter, J. D., Bassell, G. J. & Klann, E. Dysregulation and restoration of translational homeostasis in fragile X syndrome. Nat. Rev. Neurosci. 16, 595\u2013605 (2015).","journal-title":"Nat. Rev. Neurosci."},{"key":"913_CR3","doi-asserted-by":"publisher","first-page":"825","DOI":"10.1016\/j.neuron.2013.02.022","volume":"77","author":"DL Nelson","year":"2013","unstructured":"Nelson, D. L., Orr, H. T. & Warren, S. T. The unstable repeats\u2014three evolving faces of neurological disease. Neuron 77, 825\u2013843 (2013).","journal-title":"Neuron"},{"key":"913_CR4","doi-asserted-by":"publisher","first-page":"17065","DOI":"10.1038\/nrdp.2017.65","volume":"3","author":"RJ Hagerman","year":"2017","unstructured":"Hagerman, R. J. et al. Fragile X syndrome. Nat. Rev. Dis. Prim. 3, 17065 (2017).","journal-title":"Nat. Rev. Dis. Prim."},{"key":"913_CR5","doi-asserted-by":"publisher","first-page":"373","DOI":"10.1038\/nature12517","volume":"501","author":"MA Lancaster","year":"2013","unstructured":"Lancaster, M. A. et al. Cerebral organoids model human brain development and microcephaly. Nature 501, 373\u2013379 (2013).","journal-title":"Nature"},{"key":"913_CR6","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1038\/nmeth.3415","volume":"12","author":"AM Pasca","year":"2015","unstructured":"Pasca, A. M. et al. Functional cortical neurons and astrocytes from human pluripotent stem cells in 3D culture. Nat. Methods 12, 671\u2013678 (2015).","journal-title":"Nat. Methods"},{"key":"913_CR7","doi-asserted-by":"publisher","first-page":"1238","DOI":"10.1016\/j.cell.2016.04.032","volume":"165","author":"X Qian","year":"2016","unstructured":"Qian, X. et al. Brain-region-specific organoids using mini-bioreactors for modeling ZIKV exposure. Cell 165, 1238\u20131254 (2016).","journal-title":"Cell"},{"key":"913_CR8","doi-asserted-by":"publisher","first-page":"e0165499","DOI":"10.1371\/journal.pone.0165499","volume":"11","author":"N Xie","year":"2016","unstructured":"Xie, N. et al. Reactivation of FMR1 by CRISPR\/Cas9-mediated deletion of the expanded CGG-repeat of the fragile X chromosome. PLoS ONE 11, e0165499 (2016).","journal-title":"PLoS ONE"},{"key":"913_CR9","doi-asserted-by":"publisher","first-page":"743","DOI":"10.1016\/j.neuroimage.2018.12.043","volume":"188","author":"I Kostovic","year":"2019","unstructured":"Kostovic, I., Sedmak, G. & Judas, M. Neural histology and neurogenesis of the human fetal and infant brain. Neuroimage 188, 743\u2013773 (2019).","journal-title":"Neuroimage"},{"key":"913_CR10","doi-asserted-by":"publisher","first-page":"867","DOI":"10.1097\/00005072-199908000-00009","volume":"58","author":"C Agulhon","year":"1999","unstructured":"Agulhon, C. et al. Expression of FMR1, FXR1, and FXR2 genes in human prenatal tissues. J. Neuropathol. Exp. Neurol. 58, 867\u2013880 (1999).","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"913_CR11","doi-asserted-by":"publisher","first-page":"1315","DOI":"10.1093\/hmg\/6.8.1315","volume":"6","author":"F Tamanini","year":"1997","unstructured":"Tamanini, F. et al. Differential expression of FMR1, FXR1 and FXR2 proteins in human brain and testis. Hum. Mol. Genet 6, 1315\u20131322 (1997).","journal-title":"Hum. Mol. Genet"},{"key":"913_CR12","doi-asserted-by":"publisher","first-page":"108991","DOI":"10.1016\/j.celrep.2021.108991","volume":"35","author":"N Raj","year":"2021","unstructured":"Raj, N. et al. Cell-type-specific profiling of human cellular models of fragile X syndrome reveal PI3K-dependent defects in translation and neurogenesis. Cell Rep. 35, 108991 (2021).","journal-title":"Cell Rep."},{"key":"913_CR13","doi-asserted-by":"publisher","first-page":"877","DOI":"10.1016\/j.cell.2017.09.003","volume":"171","author":"KJ Yoon","year":"2017","unstructured":"Yoon, K. J. et al. Temporal control of mammalian cortical neurogenesis by m6A methylation. Cell 171, 877\u2013889 (2017).","journal-title":"Cell"},{"key":"913_CR14","doi-asserted-by":"publisher","first-page":"761","DOI":"10.1016\/j.neuron.2009.08.008","volume":"63","author":"JY Kim","year":"2009","unstructured":"Kim, J. Y. et al. DISC1 regulates new neuron development in the adult brain via modulation of AKT-mTOR signaling through KIAA1212. Neuron 63, 761\u2013773 (2009).","journal-title":"Neuron"},{"key":"913_CR15","doi-asserted-by":"publisher","first-page":"777","DOI":"10.1038\/nrm1739","volume":"6","author":"M Gotz","year":"2005","unstructured":"Gotz, M. & Huttner, W. B. The cell biology of neurogenesis. Nat. Rev. Mol. Cell Biol. 6, 777\u2013788 (2005).","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"913_CR16","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/S0092-8674(00)80899-5","volume":"92","author":"JG Gleeson","year":"1998","unstructured":"Gleeson, J. G. et al. Doublecortin, a brain-specific gene mutated in human X-linked lissencephaly and double cortex syndrome, encodes a putative signaling protein. Cell 92, 63\u201372 (1998).","journal-title":"Cell"},{"key":"913_CR17","doi-asserted-by":"publisher","first-page":"766","DOI":"10.1016\/j.stem.2020.02.002","volume":"26","author":"X Qian","year":"2020","unstructured":"Qian, X. et al. Sliced human cortical organoids for modeling distinct cortical layer formation. Cell Stem Cell 26, 766\u2013781 e769 (2020).","journal-title":"Cell Stem Cell"},{"key":"913_CR18","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1385\/NI:5:1:79","volume":"5","author":"B Clancy","year":"2007","unstructured":"Clancy, B. et al. Web-based method for translating neurodevelopment from laboratory species to humans. Neuroinformatics 5, 79\u201394 (2007).","journal-title":"Neuroinformatics"},{"key":"913_CR19","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1038\/nbt.4096","volume":"36","author":"A Butler","year":"2018","unstructured":"Butler, A., Hoffman, P., Smibert, P., Papalexi, E. & Satija, R. Integrating single-cell transcriptomic data across different conditions, technologies, and species. Nat. Biotechnol. 36, 411\u2013420 (2018).","journal-title":"Nat. Biotechnol."},{"key":"913_CR20","doi-asserted-by":"publisher","first-page":"7285","DOI":"10.1073\/pnas.1507125112","volume":"112","author":"S Darmanis","year":"2015","unstructured":"Darmanis, S. et al. A survey of human brain transcriptome diversity at the single cell level. Proc. Natl Acad. Sci. USA 112, 7285\u20137290 (2015).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"913_CR21","doi-asserted-by":"publisher","first-page":"1879","DOI":"10.1038\/emboj.2012.43","volume":"31","author":"Y Tsunekawa","year":"2012","unstructured":"Tsunekawa, Y. et al. Cyclin D2 in the basal process of neural progenitors is linked to non-equivalent cell fates. EMBO J. 31, 1879\u20131892 (2012).","journal-title":"EMBO J."},{"key":"913_CR22","doi-asserted-by":"publisher","first-page":"979","DOI":"10.1038\/nmeth.4402","volume":"14","author":"X Qiu","year":"2017","unstructured":"Qiu, X. et al. Reversed graph embedding resolves complex single-cell trajectories. Nat. Methods 14, 979\u2013982 (2017).","journal-title":"Nat. Methods"},{"key":"913_CR23","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1038\/nbt.2859","volume":"32","author":"C Trapnell","year":"2014","unstructured":"Trapnell, C. et al. The dynamics and regulators of cell fate decisions are revealed by pseudotemporal ordering of single cells. Nat. Biotechnol. 32, 381\u2013386 (2014).","journal-title":"Nat. Biotechnol."},{"key":"913_CR24","doi-asserted-by":"publisher","first-page":"7746","DOI":"10.1073\/pnas.122205699","volume":"99","author":"KM Huber","year":"2002","unstructured":"Huber, K. M., Gallagher, S. M., Warren, S. T. & Bear, M. F. Altered synaptic plasticity in a mouse model of fragile X mental retardation. Proc. Natl Acad. Sci. USA 99, 7746\u20137750 (2002).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"913_CR25","doi-asserted-by":"publisher","first-page":"370","DOI":"10.1016\/j.tins.2004.04.009","volume":"27","author":"MF Bear","year":"2004","unstructured":"Bear, M. F., Huber, K. M. & Warren, S. T. The mGluR theory of fragile X mental retardation. Trends Neurosci. 27, 370\u2013377 (2004).","journal-title":"Trends Neurosci."},{"key":"913_CR26","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1016\/j.neuron.2012.03.009","volume":"74","author":"A Michalon","year":"2012","unstructured":"Michalon, A. et al. Chronic pharmacological mGlu5 inhibition corrects fragile X in adult mice. Neuron 74, 49\u201356 (2012).","journal-title":"Neuron"},{"key":"913_CR27","doi-asserted-by":"publisher","first-page":"955","DOI":"10.1016\/j.neuron.2007.12.001","volume":"56","author":"G Dolen","year":"2007","unstructured":"Dolen, G. et al. Correction of fragile X syndrome in mice. Neuron 56, 955\u2013962 (2007).","journal-title":"Neuron"},{"key":"913_CR28","doi-asserted-by":"publisher","first-page":"503","DOI":"10.1038\/npp.2017.177","volume":"43","author":"EA Youssef","year":"2018","unstructured":"Youssef, E. A. et al. Effect of the mGluR5-NAM basimglurant on behavior in adolescents and adults with fragile X syndrome in a randomized, double-blind, placebo-controlled trial: FragXis phase 2 results. Neuropsychopharmacology 43, 503\u2013512 (2018).","journal-title":"Neuropsychopharmacology"},{"key":"913_CR29","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.celrep.2015.03.004","volume":"11","author":"C Gross","year":"2015","unstructured":"Gross, C. et al. Increased expression of the PI3K enhancer PIKE mediates deficits in synaptic plasticity and behavior in fragile X syndrome. Cell Rep. 11, 1\u201310 (2015).","journal-title":"Cell Rep."},{"key":"913_CR30","doi-asserted-by":"publisher","first-page":"681","DOI":"10.1016\/j.celrep.2015.03.065","volume":"11","author":"C Gross","year":"2015","unstructured":"Gross, C. et al. Selective role of the catalytic PI3K subunit p110\u03b2 in impaired higher order cognition in fragile X syndrome. Cell Rep. 11, 681\u2013688 (2015).","journal-title":"Cell Rep."},{"key":"913_CR31","doi-asserted-by":"publisher","first-page":"324","DOI":"10.1038\/s41386-018-0150-5","volume":"44","author":"C Gross","year":"2019","unstructured":"Gross, C. et al. Isoform-selective phosphoinositide 3-kinase inhibition ameliorates a broad range of fragile X syndrome-associated deficits in a mouse model. Neuropsychopharmacology 44, 324\u2013333 (2019).","journal-title":"Neuropsychopharmacology"},{"key":"913_CR32","doi-asserted-by":"publisher","first-page":"508","DOI":"10.1038\/nmeth.3810","volume":"13","author":"EL Van Nostrand","year":"2016","unstructured":"Van Nostrand, E. L. et al. Robust transcriptome-wide discovery of RNA-binding protein binding sites with enhanced CLIP (eCLIP). Nat. Methods 13, 508\u2013514 (2016).","journal-title":"Nat. Methods"},{"key":"913_CR33","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1016\/j.cell.2011.06.013","volume":"146","author":"JC Darnell","year":"2011","unstructured":"Darnell, J. C. et al. FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism. Cell 146, 247\u2013261 (2011).","journal-title":"Cell"},{"key":"913_CR34","doi-asserted-by":"publisher","first-page":"D832","DOI":"10.1093\/nar\/gkn835","volume":"37","author":"SN Basu","year":"2009","unstructured":"Basu, S. N., Kollu, R. & Banerjee-Basu, S. AutDB: a gene reference resource for autism research. Nucleic Acids Res 37, D832\u2013D836 (2009).","journal-title":"Nucleic Acids Res"},{"key":"913_CR35","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1038\/mp.2009.93","volume":"15","author":"P Jia","year":"2010","unstructured":"Jia, P., Sun, J., Guo, A. Y. & Zhao, Z. SZGR: a comprehensive schizophrenia gene resource. Mol. Psychiatry 15, 453\u2013462 (2010).","journal-title":"Mol. Psychiatry"},{"key":"913_CR36","doi-asserted-by":"publisher","first-page":"1031","DOI":"10.1038\/ng.3623","volume":"48","author":"CL Hyde","year":"2016","unstructured":"Hyde, C. L. et al. Identification of 15 genetic loci associated with risk of major depression in individuals of European descent. Nat. Genet 48, 1031\u20131036 (2016).","journal-title":"Nat. Genet"},{"key":"913_CR37","doi-asserted-by":"publisher","first-page":"807","DOI":"10.1038\/nrg3335","volume":"13","author":"J Flint","year":"2012","unstructured":"Flint, J. & Eskin, E. Genome-wide association studies in mice. Nat. Rev. Genet 13, 807\u2013817 (2012).","journal-title":"Nat. Rev. Genet"},{"key":"913_CR38","doi-asserted-by":"publisher","first-page":"1416","DOI":"10.1101\/gr.1015703","volume":"13","author":"K Tajul-Arifin","year":"2003","unstructured":"Tajul-Arifin, K. et al. Identification and analysis of chromodomain-containing proteins encoded in the mouse transcriptome. Genome Res. 13, 1416\u20131429 (2003).","journal-title":"Genome Res."},{"key":"913_CR39","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1186\/1866-1955-6-9","volume":"6","author":"S Chenier","year":"2014","unstructured":"Chenier, S. et al. CHD2 haploinsufficiency is associated with developmental delay, intellectual disability, epilepsy and neurobehavioural problems. J. Neurodev. Disord. 6, 9 (2014).","journal-title":"J. Neurodev. Disord."},{"key":"913_CR40","doi-asserted-by":"publisher","first-page":"1180","DOI":"10.1016\/j.neuron.2018.09.049","volume":"100","author":"YJ Kim","year":"2018","unstructured":"Kim, Y. J. et al. Chd2 is necessary for neural circuit development and long-term memory. Neuron 100, 1180\u20131193 (2018).","journal-title":"Neuron"},{"key":"913_CR41","doi-asserted-by":"publisher","first-page":"979","DOI":"10.1016\/j.cell.2018.01.012","volume":"172","author":"XS Liu","year":"2018","unstructured":"Liu, X. S. et al. Rescue of fragile X syndrome neurons by DNA methylation editing of the FMR1 gene. Cell 172, 979\u2013992 (2018).","journal-title":"Cell"},{"key":"913_CR42","doi-asserted-by":"publisher","first-page":"2143","DOI":"10.1111\/ejn.14660","volume":"51","author":"JD Graef","year":"2020","unstructured":"Graef, J. D. et al. Partial FMRP expression is sufficient to normalize neuronal hyperactivity in fragile X neurons. Eur. J. Neurosci. 51, 2143\u20132157 (2020).","journal-title":"Eur. J. Neurosci."},{"key":"913_CR43","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1016\/j.ydbio.2012.11.031","volume":"374","author":"M Telias","year":"2013","unstructured":"Telias, M., Segal, M. & Ben-Yosef, D. Neural differentiation of fragile X human embryonic stem cells reveals abnormal patterns of development despite successful neurogenesis. Dev. Biol. 374, 32\u201345 (2013).","journal-title":"Dev. Biol."},{"key":"913_CR44","doi-asserted-by":"publisher","first-page":"1777","DOI":"10.1089\/scd.2014.0030","volume":"23","author":"ME Doers","year":"2014","unstructured":"Doers, M. E. et al. iPSC-derived forebrain neurons from FXS individuals show defects in initial neurite outgrowth. Stem Cells Dev. 23, 1777\u20131787 (2014).","journal-title":"Stem Cells Dev."},{"key":"913_CR45","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1016\/j.stemcr.2014.10.015","volume":"4","author":"T Halevy","year":"2015","unstructured":"Halevy, T., Czech, C. & Benvenisty, N. Molecular mechanisms regulating the defects in fragile X syndrome neurons derived from human pluripotent stem cells. Stem Cell Rep. 4, 37\u201346 (2015).","journal-title":"Stem Cell Rep."},{"key":"913_CR46","doi-asserted-by":"publisher","first-page":"1247125","DOI":"10.1126\/science.1247125","volume":"345","author":"MA Lancaster","year":"2014","unstructured":"Lancaster, M. A. & Knoblich, J. A. Organogenesis in a dish: modeling development and disease using organoid technologies. Science 345, 1247125 (2014).","journal-title":"Science"},{"key":"913_CR47","doi-asserted-by":"publisher","first-page":"520","DOI":"10.1016\/j.stem.2013.04.009","volume":"12","author":"Y Sasai","year":"2013","unstructured":"Sasai, Y. Next-generation regenerative medicine: organogenesis from stem cells in 3D culture. Cell Stem Cell 12, 520\u2013530 (2013).","journal-title":"Cell Stem Cell"},{"key":"913_CR48","doi-asserted-by":"crossref","unstructured":"Gonzalez, C. et al. Modeling amyloid beta and tau pathology in human cerebral organoids. Mol Psychiatry 23, 2363\u20132374 (2018).","DOI":"10.1038\/s41380-018-0229-8"},{"key":"913_CR49","doi-asserted-by":"publisher","first-page":"1141","DOI":"10.1016\/j.neuron.2018.05.008","volume":"98","author":"YT Lin","year":"2018","unstructured":"Lin, Y. T. et al. APOE4 causes widespread molecular and cellular alterations associated with Alzheimer\u2019s disease phenotypes in human iPSC-derived brain cell types. Neuron 98, 1141\u20131154 (2018).","journal-title":"Neuron"},{"key":"913_CR50","doi-asserted-by":"publisher","first-page":"9917","DOI":"10.1523\/JNEUROSCI.0621-17.2017","volume":"37","author":"J Seo","year":"2017","unstructured":"Seo, J. et al. Inhibition of p25\/Cdk5 attenuates tauopathy in mouse and iPSC models of frontotemporal dementia. J. Neurosci. 37, 9917\u20139924 (2017).","journal-title":"J. Neurosci."},{"key":"913_CR51","doi-asserted-by":"publisher","first-page":"e0161969","DOI":"10.1371\/journal.pone.0161969","volume":"11","author":"WK Raja","year":"2016","unstructured":"Raja, W. K. et al. Self-organizing 3D human neural tissue derived from induced pluripotent stem cells recapitulate Alzheimer\u2019s disease phenotypes. PLoS ONE 11, e0161969 (2016).","journal-title":"PLoS ONE"},{"key":"913_CR52","doi-asserted-by":"publisher","first-page":"e0163072","DOI":"10.1371\/journal.pone.0163072","volume":"11","author":"HK Lee","year":"2016","unstructured":"Lee, H. K. et al. Three dimensional human neuro-spheroid model of Alzheimer\u2019s disease based on differentiated induced pluripotent stem cells. PLoS ONE 11, e0163072 (2016).","journal-title":"PLoS ONE"},{"key":"913_CR53","doi-asserted-by":"publisher","first-page":"923","DOI":"10.2337\/db13-0717","volume":"63","author":"L Shang","year":"2014","unstructured":"Shang, L. et al. \u03b2-cell dysfunction due to increased ER stress in a stem cell model of Wolfram syndrome. Diabetes 63, 923\u2013933 (2014).","journal-title":"Diabetes"},{"key":"913_CR54","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1016\/j.stemcr.2016.01.007","volume":"6","author":"AK Teo","year":"2016","unstructured":"Teo, A. K. et al. Early developmental perturbations in a human stem cell model of MODY5\/HNF1B pancreatic hypoplasia. Stem Cell Rep. 6, 357\u2013367 (2016).","journal-title":"Stem Cell Rep."},{"key":"913_CR55","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-016-0028-x","volume":"7","author":"M Nishita","year":"2017","unstructured":"Nishita, M. et al. Ror2 signaling regulates Golgi structure and transport through IFT20 for tumor invasiveness. Sci. Rep. 7, 1 (2017).","journal-title":"Sci. Rep."},{"key":"913_CR56","doi-asserted-by":"publisher","first-page":"481","DOI":"10.1111\/jdi.12727","volume":"9","author":"Y Hosokawa","year":"2017","unstructured":"Hosokawa, Y. et al. Insulin-producing cells derived from \u2018induced pluripotent stem cells\u2019 of patients with fulminant type 1 diabetes: vulnerability to cytokine insults and increased expression of apoptosis-related genes. J. Diabetes Investig. 9, 481\u2013493 (2017).","journal-title":"J. Diabetes Investig."},{"key":"913_CR57","doi-asserted-by":"publisher","first-page":"326","DOI":"10.1016\/j.stem.2016.07.002","volume":"19","author":"H Zeng","year":"2016","unstructured":"Zeng, H. et al. An isogenic human ESC platform for functional evaluation of genome-wide-association-study-identified diabetes genes and drug discovery. Cell Stem Cell 19, 326\u2013340 (2016).","journal-title":"Cell Stem Cell"},{"key":"913_CR58","doi-asserted-by":"publisher","first-page":"325","DOI":"10.1016\/j.neuron.2012.07.022","volume":"76","author":"A Bhattacharya","year":"2012","unstructured":"Bhattacharya, A. et al. Genetic removal of p70 S6 kinase 1 corrects molecular, synaptic, and behavioral phenotypes in fragile X syndrome mice. Neuron 76, 325\u2013337 (2012).","journal-title":"Neuron"},{"key":"913_CR59","doi-asserted-by":"crossref","unstructured":"Bhattacharya, A. et al. Targeting translation control with p70 S6 kinase 1 inhibitors to reverse phenotypes in fragile X syndrome mice. Neuropsychopharmacology 41, 1991\u20132000 (2015).","DOI":"10.1038\/npp.2015.369"},{"key":"913_CR60","doi-asserted-by":"publisher","first-page":"336","DOI":"10.2119\/molmed.2011.00363","volume":"18","author":"C Gross","year":"2012","unstructured":"Gross, C. & Bassell, G. J. Excess protein synthesis in FXS patient lymphoblastoid cells can be rescued with a p110\u03b2-selective inhibitor. Mol. Med 18, 336\u2013345 (2012).","journal-title":"Mol. Med"},{"key":"913_CR61","doi-asserted-by":"publisher","first-page":"10624","DOI":"10.1523\/JNEUROSCI.0402-10.2010","volume":"30","author":"C Gross","year":"2010","unstructured":"Gross, C. et al. Excess phosphoinositide 3-kinase subunit synthesis and activity as a novel therapeutic target in fragile X syndrome. J. Neurosci. 30, 10624\u201310638 (2010).","journal-title":"J. Neurosci."},{"key":"913_CR62","doi-asserted-by":"publisher","first-page":"332","DOI":"10.1111\/j.1601-183X.2012.00768.x","volume":"11","author":"CA Hoeffer","year":"2012","unstructured":"Hoeffer, C. A. et al. Altered mTOR signaling and enhanced CYFIP2 expression levels in subjects with fragile X syndrome. Genes Brain Behav. 11, 332\u2013341 (2012).","journal-title":"Genes Brain Behav."},{"key":"913_CR63","doi-asserted-by":"crossref","unstructured":"Kumari, D. et al. Identification of fragile X syndrome specific molecular markers in human fibroblasts: a useful model to test the efficacy of therapeutic drugs. Hum. Mutat. 35, 1485\u20131494 (2014).","DOI":"10.1002\/humu.22699"},{"key":"913_CR64","doi-asserted-by":"publisher","first-page":"694","DOI":"10.1523\/JNEUROSCI.3696-09.2010","volume":"30","author":"A Sharma","year":"2010","unstructured":"Sharma, A. et al. Dysregulation of mTOR signaling in fragile X syndrome. J. Neurosci. 30, 694\u2013702 (2010).","journal-title":"J. Neurosci."},{"key":"913_CR65","doi-asserted-by":"publisher","first-page":"711","DOI":"10.1007\/s12035-018-1122-9","volume":"56","author":"TC Dockendorff","year":"2019","unstructured":"Dockendorff, T. C. & Labrador, M. The fragile X protein and genome function. Mol. Neurobiol. 56, 711\u2013721 (2019).","journal-title":"Mol. Neurobiol."},{"key":"913_CR66","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1002\/1096-8628(200022)97:2<153::AID-AJMG7>3.0.CO;2-M","volume":"97","author":"B Bardoni","year":"2000","unstructured":"Bardoni, B., Mandel, J. L. & Fisch, G. S. FMR1 gene and fragile X syndrome. Am. J. Med. Genet 97, 153\u2013163 (2000).","journal-title":"Am. J. Med. Genet"},{"key":"913_CR67","doi-asserted-by":"publisher","first-page":"160","DOI":"10.2741\/s455","volume":"8","author":"ML Castr\u00e9n","year":"2016","unstructured":"Castr\u00e9n, M. L. Cortical neurogenesis in fragile X syndrome. Front. Biosci. (Schol. Ed.). 8, 160\u2013168 (2016).","journal-title":"Front. Biosci. (Schol. Ed.)."},{"key":"913_CR68","doi-asserted-by":"publisher","first-page":"601","DOI":"10.1007\/s00439-002-0723-5","volume":"110","author":"R Willemsen","year":"2002","unstructured":"Willemsen, R., Bontekoe, C. J., Severijnen, L. A. & Oostra, B. A. Timing of the absence of FMR1 expression in full mutation chorionic villi. Hum. Genet. 110, 601\u2013605 (2002).","journal-title":"Hum. Genet."},{"key":"913_CR69","first-page":"3936","volume":"27","author":"F Zhang","year":"2018","unstructured":"Zhang, F. et al. Fragile X mental retardation protein modulates the stability of its m6A-marked messenger RNA targets. Hum. Mol. Genet 27, 3936\u20133950 (2018).","journal-title":"Hum. Mol. Genet"},{"key":"913_CR70","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1016\/j.brainres.2017.04.013","volume":"1666","author":"M Sourial","year":"2017","unstructured":"Sourial, M. & Doering, L. C. Abnormal neural precursor cell regulation in the early postnatal fragile X mouse hippocampus. Brain Res 1666, 58\u201369 (2017).","journal-title":"Brain Res"},{"key":"913_CR71","doi-asserted-by":"publisher","first-page":"250","DOI":"10.1016\/j.nbd.2008.10.010","volume":"33","author":"TA Tervonen","year":"2009","unstructured":"Tervonen, T. A. et al. Aberrant differentiation of glutamatergic cells in neocortex of mouse model for fragile X syndrome. Neurobiol. Dis. 33, 250\u2013259 (2009).","journal-title":"Neurobiol. Dis."},{"key":"913_CR72","doi-asserted-by":"publisher","first-page":"17834","DOI":"10.1073\/pnas.0508995102","volume":"102","author":"M Castren","year":"2005","unstructured":"Castren, M. et al. Altered differentiation of neural stem cells in fragile X syndrome. Proc. Natl Acad. Sci. USA 102, 17834\u201317839 (2005).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"913_CR73","doi-asserted-by":"publisher","first-page":"374","DOI":"10.1002\/stem.2505","volume":"35","author":"O Khalfallah","year":"2017","unstructured":"Khalfallah, O. et al. Depletion of the fragile X mental retardation protein in embryonic stem cells alters the kinetics of neurogenesis. Stem Cells 35, 374\u2013385 (2017).","journal-title":"Stem Cells"},{"key":"913_CR74","doi-asserted-by":"publisher","first-page":"e1000898","DOI":"10.1371\/journal.pgen.1000898","volume":"6","author":"Y Luo","year":"2010","unstructured":"Luo, Y. et al. Fragile X mental retardation protein regulates proliferation and differentiation of adult neural stem\/progenitor cells. PLoS Genet. 6, e1000898 (2010).","journal-title":"PLoS Genet."},{"key":"913_CR75","doi-asserted-by":"publisher","first-page":"375","DOI":"10.1016\/j.cell.2015.06.034","volume":"162","author":"J Mariani","year":"2015","unstructured":"Mariani, J. et al. FOXG1-dependent dysregulation of GABA\/glutamate neuron differentiation in autism spectrum disorders. Cell 162, 375\u2013390 (2015).","journal-title":"Cell"},{"key":"913_CR76","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1038\/nature22330","volume":"545","author":"F Birey","year":"2017","unstructured":"Birey, F. et al. Assembly of functionally integrated human forebrain spheroids. Nature 545, 54\u201359 (2017).","journal-title":"Nature"},{"key":"913_CR77","doi-asserted-by":"publisher","first-page":"414","DOI":"10.1038\/nature13716","volume":"515","author":"Z Wen","year":"2014","unstructured":"Wen, Z. et al. Synaptic dysregulation in a human iPS cell model of mental disorders. Nature 515, 414\u2013418 (2014).","journal-title":"Nature"},{"key":"913_CR78","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8","volume":"15","author":"MI Love","year":"2014","unstructured":"Love, M. I., Huber, W. & Anders, S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15, 550 (2014).","journal-title":"Genome Biol."},{"key":"913_CR79","doi-asserted-by":"publisher","first-page":"383","DOI":"10.1016\/j.stem.2017.07.007","volume":"21","author":"Y Xiang","year":"2017","unstructured":"Xiang, Y. et al. Fusion of regionally specified hPSC-derived organoids models human brain development and interneuron migration. Cell Stem Cell 21, 383\u2013398 (2017).","journal-title":"Cell Stem Cell"},{"key":"913_CR80","doi-asserted-by":"crossref","unstructured":"Xiang, Y. et al. hESC-derived thalamic organoids form reciprocal projections when fused with cortical organoids. Cell Stem Cell 24, 487\u2013497 (2019).","DOI":"10.1016\/j.stem.2018.12.015"},{"key":"913_CR81","doi-asserted-by":"publisher","first-page":"1434","DOI":"10.1038\/nsmb.2699","volume":"20","author":"MT Lovci","year":"2013","unstructured":"Lovci, M. T. et al. Rbfox proteins regulate alternative mRNA splicing through evolutionarily conserved RNA bridges. Nat. Struct. Mol. Biol. 20, 1434\u20131442 (2013).","journal-title":"Nat. Struct. Mol. Biol."},{"key":"913_CR82","doi-asserted-by":"publisher","first-page":"W214","DOI":"10.1093\/nar\/gkq537","volume":"38","author":"D Warde-Farley","year":"2010","unstructured":"Warde-Farley, D. et al. The GeneMANIA prediction server: biological network integration for gene prioritization and predicting gene function. Nucleic Acids Res. 38, W214\u2013W220 (2010).","journal-title":"Nucleic Acids Res."}],"container-title":["Nature Neuroscience"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41593-021-00913-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41593-021-00913-6","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41593-021-00913-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,29]],"date-time":"2021-09-29T11:21:19Z","timestamp":1632914479000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41593-021-00913-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,19]]},"references-count":82,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2021,10]]}},"alternative-id":["913"],"URL":"https:\/\/doi.org\/10.1038\/s41593-021-00913-6","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.740667027.793589648","asserted-by":"object"}]},"ISSN":["1097-6256","1546-1726"],"issn-type":[{"value":"1097-6256","type":"print"},{"value":"1546-1726","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,19]]},"assertion":[{"value":"12 April 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 July 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 August 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}