Thalamocortical organoids enable in  vitro modeling of 22q11.2 microdeletion associated with neuropsychiatric disorders

Cell Stem Cell. 2024 Feb 13:S1934-5909(24)00040-7. doi: 10.1016/j.stem.2024.01.010. Online ahead of print.ABSTRACTThalamic 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.PMID:38382530 | DOI:10.1016/j.stem.2024.01.010
Source: Cell Stem Cell - Category: Stem Cells Authors: Source Type: research