Bansal, PrakharBanda, Erin C.Glatt-Deeley, Heather R.Stoddard, Christopher E.Linsley, Jeremy W.Arora, NehaDeleschaux, CécileAhern, Darcy T.Kondaveeti, YuvabharathMassey, Rachael E.Nicouleau, MichaelWang, ShijieSabariego Navarro, MiguelDierssen, MaraFinkbeiner, StevenPinter, Stefan F.2024-09-132024-09-132024Bansal P, Banda EC, Glatt-Deeley HR, Stoddard CE, Linsley JW, Arora N, et al. A dynamic in vitro model of Down syndrome neurogenesis with trisomy 21 gene dosage correction. Sci Adv. 2024 Jun 7;10(23):eadj0385. DOI: 10.1126/sciadv.adj03852375-2548http://hdl.handle.net/10230/61083Excess gene dosage from chromosome 21 (chr21) causes Down syndrome (DS), spanning developmental and acute phenotypes in terminal cell types. Which phenotypes remain amenable to intervention after development is unknown. To address this question in a model of DS neurogenesis, we derived trisomy 21 (T21) human induced pluripotent stem cells (iPSCs) alongside, otherwise, isogenic euploid controls from mosaic DS fibroblasts and equipped one chr21 copy with an inducible XIST transgene. Monoallelic chr21 silencing by XIST is near-complete and irreversible in iPSCs. Differential expression reveals that T21 neural lineages and iPSCs share suppressed translation and mitochondrial pathways and activate cellular stress responses. When XIST is induced before the neural progenitor stage, T21 dosage correction suppresses a pronounced skew toward astrogenesis in neural differentiation. Because our transgene remains inducible in postmitotic T21 neurons and astrocytes, we demonstrate that XIST efficiently represses genes even after terminal differentiation, which will empower exploration of cell type-specific T21 phenotypes that remain responsive to chr21 dosage.application/pdfengCopyright © 2024 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license (https://creativecommons.org/licenses/by-nc/4.0/), which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.Down, Síndrome deCromosoma humà 21info:eu-repo/semantics/articlehttp://dx.doi.org/10.1126/sciadv.adj0385info:eu-repo/semantics/openAccess