biostudies-literatureShin DNIMH NIH HHSNINDS NIH HHSNIHCIHR421-432.e8https://www.ebi.ac.uk/biostudies/studies/S-EPMC10939828biostudies-literatureUnknown31(3)Thalamic dysfunction has been implicated in multiple psychiatric disorders. We sought to study the mechanisms by which abnormalities emerge in the context of the 22q11.2 microdeletion, which confers significant genetic risk for psychiatric disorders. We investigated early stages of human thalamus development using human pluripotent stem cell-derived organoids and show that the 22q11.2 microdeletion underlies widespread transcriptional dysregulation associated with psychiatric disorders in thalamic neurons and glia, including elevated expression of FOXP2. Using an organoid co-culture model, we demonstrate that the 22q11.2 microdeletion mediates an overgrowth of thalamic axons in a FOXP2-dependent manner. Finally, we identify ROBO2 as a candidate molecular mediator of the effects of FOXP2 overexpression on thalamic axon overgrowth. Together, our study suggests that early steps in thalamic development are dysregulated in a model of genetic risk for schizophrenia and contribute to neural phenotypes in 22q11.2 deletion syndrome.Cell stem cellThalamocortical organoids enable in vitro modeling of 22q11.2 microdeletion associated with neuropsychiatric disorders.PMC10939828R37 MH085953R01 MH122681R01 MH129858R01 NS123263R01 MH085953U01 MH119690R21 MH116473U01 MH115747R01 MH125516U01 MH122681R01 MH128364RF1 MH121268Bhaduri ABearden CENowakowski TJCadwell CRKim CNHennick KMPollen AAPopova GWang JCRoss JPavlovic BJWiita APJacquemont SMoreau CKeefe MGWigdor EMFrost NAHaussler DAllen DELeonard RShin DSohal VSDonohue KCSanders SJParanjape NWu SRLarson HHfalseThalamocortical organoids enable in vitro modeling of 22q11.2 microdeletion associated with neuropsychiatric disorders.Thalamic dysfunction has been implicated in multiple psychiatric disorders. We sought to study the mechanisms by which abnormalities emerge in the context of the 22q11.2 microdeletion, which confers significant genetic risk for psychiatric disorders. We investigated early stages of human thalamus development using human pluripotent stem cell-derived organoids and show that the 22q11.2 microdeletion underlies widespread transcriptional dysregulation associated with psychiatric disorders in thalamic neurons and glia, including elevated expression of FOXP2. Using an organoid co-culture model, we demonstrate that the 22q11.2 microdeletion mediates an overgrowth of thalamic axons in a FOXP2-dependent manner. Finally, we identify ROBO2 as a candidate molecular mediator of the effects of FOXP2 overexpression on thalamic axon overgrowth. Together, our study suggests that early steps in thalamic development are dysregulated in a model of genetic risk for schizophrenia and contribute to neural phenotypes in 22q11.2 deletion syndrome.2024-01-01T00:00:00Z2024 Mar2026-06-01T22:04:41.149Z2025-04-04T13:46:31.316ZS-EPMC109398283838253010.1016/j.stem.2024.01.010