A dynamic in vitro model of Down syndrome neurogenesis with trisomy 21 gene dosage correction-Reference-Cited by-同舟云学术

A dynamic in vitro model of Down syndrome neurogenesis with trisomy 21 gene dosage correction

Published:2024-06-07 Issue:23 Volume:10 Page:
ISSN:2375-2548
Container-title:Science Advances
language:en
Short-container-title:Sci. Adv.

Author:

Bansal Prakhar¹²^ORCID,Banda Erin C.²^ORCID,Glatt-Deeley Heather R.²^ORCID,Stoddard Christopher E.³^ORCID,Linsley Jeremy W.⁴⁵^ORCID,Arora Neha⁴^ORCID,Deleschaux Cécile²^ORCID,Ahern Darcy T.¹²^ORCID,Kondaveeti Yuvabharath²^ORCID,Massey Rachael E.¹²⁶^ORCID,Nicouleau Michael²,Wang Shijie⁴^ORCID,Sabariego-Navarro Miguel⁷^ORCID,Dierssen Mara⁷⁸⁹¹⁰^ORCID,Finkbeiner Steven⁴⁵¹¹¹²^ORCID,Pinter Stefan F.¹²⁶^ORCID

Affiliation:

1. Graduate Program in Genetics and Developmental Biology, UCONN Health, University of Connecticut, Farmington, CT, USA.

2. Department of Genetics and Genome Sciences, UCONN Health, University of Connecticut, Farmington, CT, USA.

3. Cell and Genome Engineering Core, UCONN Health, University of Connecticut, Farmington, CT, USA.

4. Center for Systems and Therapeutics, Gladstone Institutes, San Francisco, CA, USA.

5. Taube/Koret Center for Neurodegenerative Disease, Gladstone Institutes, San Francisco, CA, USA.

6. Institute for Systems Genomics, University of Connecticut, Farmington, CT, USA.

7. Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain.

8. Universitat Pompeu Fabra (UPF), Barcelona, Spain.

9. Human Pharmacology and Clinical Neurosciences Research Group, Neurosciences Research Program, Hospital Del Mar Medical Research Institute (IMIM), Barcelona, Spain.

10. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.

11. Departments of Neurology and Physiology, University of California San Francisco, San Francisco, CA, USA.

12. Neuroscience and Biomedical Sciences Graduate Programs, University of California San Francisco, San Francisco, CA, USA.

Abstract

Excess 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.

Publisher

American Association for the Advancement of Science (AAAS)

Link

https://www.science.org/doi/pdf/10.1126/sciadv.adj0385

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