A human isogenic iPSC-derived cell line panel identifies major regulators of aberrant astrocyte proliferation in Down syndrome
| Autor: | Katsuya Hirata, Hidetaka Yoshimatsu, Akira Tanave, Kenta Sumiyama, Haruna Kusakabe, Keiichi Ozono, Nobutoshi Nawa, Kimihiko Banno, Toshihiko Nambara, Keiji Kawatani, Yasuji Kitabatake, Hidetoshi Taniguchi, Hitomi Arahori |
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| Rok vydání: | 2021 |
| Předmět: |
Male
0301 basic medicine QH301-705.5 Blotting Western Induced Pluripotent Stem Cells Gene Dosage Medicine (miscellaneous) Biology Gene dosage Article General Biochemistry Genetics and Molecular Biology Cell Line 03 medical and health sciences 0302 clinical medicine Precursor cell medicine Humans Gene silencing Gene Silencing Biology (General) Induced pluripotent stem cell In Situ Hybridization Fluorescence Cell Proliferation Gene Editing Developmental disorders Infant Newborn Isogenic human disease models Paediatric neurological disorders Cell biology 030104 developmental biology medicine.anatomical_structure Astrocytes XIST Down Syndrome General Agricultural and Biological Sciences Chromosome 21 030217 neurology & neurosurgery Astrocyte |
| Zdroj: | Communications Biology Communications Biology, Vol 4, Iss 1, Pp 1-15 (2021) |
| ISSN: | 2399-3642 |
| DOI: | 10.1038/s42003-021-02242-7 |
| Popis: | Astrocytes exert adverse effects on the brains of individuals with Down syndrome (DS). Although a neurogenic-to-gliogenic shift in the fate-specification step has been reported, the mechanisms and key regulators underlying the accelerated proliferation of astrocyte precursor cells (APCs) in DS remain elusive. Here, we established a human isogenic cell line panel based on DS-specific induced pluripotent stem cells, the XIST-mediated transcriptional silencing system in trisomic chromosome 21, and genome/chromosome-editing technologies to eliminate phenotypic fluctuations caused by genetic variation. The transcriptional responses of genes observed upon XIST induction and/or downregulation are not uniform, and only a small subset of genes show a characteristic expression pattern, which is consistent with the proliferative phenotypes of DS APCs. Comparative analysis and experimental verification using gene modification reveal dose-dependent proliferation-promoting activity of DYRK1A and PIGP on DS APCs. Our collection of human isogenic cell lines provides a comprehensive set of cellular models for further DS investigations. Keiji Kawatani et al. developed a panel of Down syndrome (DS) isogenic astrocytes derived from iPSCs to observe the consequence of DS on astrocyte precursor proliferation, differentiation, and gene expression. Their results suggest a dose-dependent effect of DYRK1A and PIGP on DS-derived astrocyte precursor proliferation, and represent a valuable resource and cellular model for future DS research. |
| Databáze: | OpenAIRE |
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