Imaging-based chemical screening reveals activity-dependent neural differentiation of pluripotent stem cells
Mammalian pluripotent stem cells (PSCs) represent an important venue for understanding basic principles regulating tissue-specific differentiation and discovering new tools that may facilitate clinical applications. Mechanisms that direct neural differentiation of PSCs involve growth factor signalin...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2013-09-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/00508 |
| _version_ | 1811180604720414720 |
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| author | Yaping Sun Zhiqiang Dong Taihao Jin Kean-Hooi Ang Miller Huang Kelly M Haston Jisong Peng Tao P Zhong Steven Finkbeiner William A Weiss Michelle R Arkin Lily Y Jan Su Guo |
| author_facet | Yaping Sun Zhiqiang Dong Taihao Jin Kean-Hooi Ang Miller Huang Kelly M Haston Jisong Peng Tao P Zhong Steven Finkbeiner William A Weiss Michelle R Arkin Lily Y Jan Su Guo |
| author_sort | Yaping Sun |
| collection | DOAJ |
| description | Mammalian pluripotent stem cells (PSCs) represent an important venue for understanding basic principles regulating tissue-specific differentiation and discovering new tools that may facilitate clinical applications. Mechanisms that direct neural differentiation of PSCs involve growth factor signaling and transcription regulation. However, it is unknown whether and how electrical activity influences this process. Here we report a high throughput imaging-based screen, which uncovers that selamectin, an anti-helminthic therapeutic compound with reported activity on invertebrate glutamate-gated chloride channels, promotes neural differentiation of PSCs. We show that selamectin’s pro-neurogenic activity is mediated by γ2-containing GABAA receptors in subsets of neural rosette progenitors, accompanied by increased proneural and lineage-specific transcription factor expression and cell cycle exit. In vivo, selamectin promotes neurogenesis in developing zebrafish. Our results establish a chemical screening platform that reveals activity-dependent neural differentiation from PSCs. Compounds identified in this and future screening might prove therapeutically beneficial for treating neurodevelopmental or neurodegenerative disorders. |
| first_indexed | 2024-04-11T09:06:08Z |
| format | Article |
| id | doaj.art-620bb42bdd414c208645954b5baae185 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T09:06:08Z |
| publishDate | 2013-09-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-620bb42bdd414c208645954b5baae1852022-12-22T04:32:37ZengeLife Sciences Publications LtdeLife2050-084X2013-09-01210.7554/eLife.00508Imaging-based chemical screening reveals activity-dependent neural differentiation of pluripotent stem cellsYaping Sun0Zhiqiang Dong1Taihao Jin2Kean-Hooi Ang3Miller Huang4Kelly M Haston5Jisong Peng6Tao P Zhong7Steven Finkbeiner8William A Weiss9Michelle R Arkin10Lily Y Jan11Su Guo12Department of Bioengineering and Therapeutic Science, University of California, San Francisco, San Francisco, United States; Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, United States; Programs in Human Genetics and Biological Sciences, University of California, San Francisco, San Francisco, United StatesDepartment of Bioengineering and Therapeutic Science, University of California, San Francisco, San Francisco, United States; Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, United States; Programs in Human Genetics and Biological Sciences, University of California, San Francisco, San Francisco, United StatesDepartment of Physiology, University of California, San Francisco, San Francisco, United States; Department of Biochemistry, University of California, San Francisco, San Francisco, United States; Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United StatesDepartment of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States; Small Molecule Discovery Center, University of California, San Francisco, San Francisco, United StatesDepartment of Neurology, University of California, San Francisco, San Francisco, United States; Department of Neurological Surgery, University of California, San Francisco, San Francisco, United States; Department of Pediatrics, University of California, San Francisco, San Francisco, United StatesDepartment of Physiology, University of California, San Francisco, San Francisco, United States; Department of Neurology, University of California, San Francisco, San Francisco, United StatesDepartment of Bioengineering and Therapeutic Science, University of California, San Francisco, San Francisco, United States; Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, United States; Programs in Human Genetics and Biological Sciences, University of California, San Francisco, San Francisco, United StatesState Key Laboratory of Genetic Engineering, Department of Genetics, Fudan University School of Life Sciences, Shanghai, ChinaDepartment of Physiology, University of California, San Francisco, San Francisco, United States; Department of Biochemistry, University of California, San Francisco, San Francisco, United States; Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States; Department of Neurology, University of California, San Francisco, San Francisco, United States; Keck Foundation Program in Brain Cell Engineering, Roddenberry Center for Stem Cell Biology and Medicine, Gladstone Institutes of Neurological Disease, San Francisco, United States; Taube–Koret Center for Neurodegenerative Disease Research, San Francisco, United StatesDepartment of Neurology, University of California, San Francisco, San Francisco, United States; Department of Neurological Surgery, University of California, San Francisco, San Francisco, United States; Department of Pediatrics, University of California, San Francisco, San Francisco, United StatesDepartment of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States; Small Molecule Discovery Center, University of California, San Francisco, San Francisco, United StatesDepartment of Physiology, University of California, San Francisco, San Francisco, United States; Department of Biochemistry, University of California, San Francisco, San Francisco, United States; Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United StatesDepartment of Bioengineering and Therapeutic Science, University of California, San Francisco, San Francisco, United States; Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, United States; Programs in Human Genetics and Biological Sciences, University of California, San Francisco, San Francisco, United States; State Key Laboratory of Genetic Engineering, Department of Genetics, Fudan University School of Life Sciences, Shanghai, ChinaMammalian pluripotent stem cells (PSCs) represent an important venue for understanding basic principles regulating tissue-specific differentiation and discovering new tools that may facilitate clinical applications. Mechanisms that direct neural differentiation of PSCs involve growth factor signaling and transcription regulation. However, it is unknown whether and how electrical activity influences this process. Here we report a high throughput imaging-based screen, which uncovers that selamectin, an anti-helminthic therapeutic compound with reported activity on invertebrate glutamate-gated chloride channels, promotes neural differentiation of PSCs. We show that selamectin’s pro-neurogenic activity is mediated by γ2-containing GABAA receptors in subsets of neural rosette progenitors, accompanied by increased proneural and lineage-specific transcription factor expression and cell cycle exit. In vivo, selamectin promotes neurogenesis in developing zebrafish. Our results establish a chemical screening platform that reveals activity-dependent neural differentiation from PSCs. Compounds identified in this and future screening might prove therapeutically beneficial for treating neurodevelopmental or neurodegenerative disorders.https://elifesciences.org/articles/00508chemical geneticsmall molecule toolcellular differentiationdopaminergic neuronpluripotent stem cell |
| spellingShingle | Yaping Sun Zhiqiang Dong Taihao Jin Kean-Hooi Ang Miller Huang Kelly M Haston Jisong Peng Tao P Zhong Steven Finkbeiner William A Weiss Michelle R Arkin Lily Y Jan Su Guo Imaging-based chemical screening reveals activity-dependent neural differentiation of pluripotent stem cells eLife chemical genetic small molecule tool cellular differentiation dopaminergic neuron pluripotent stem cell |
| title | Imaging-based chemical screening reveals activity-dependent neural differentiation of pluripotent stem cells |
| title_full | Imaging-based chemical screening reveals activity-dependent neural differentiation of pluripotent stem cells |
| title_fullStr | Imaging-based chemical screening reveals activity-dependent neural differentiation of pluripotent stem cells |
| title_full_unstemmed | Imaging-based chemical screening reveals activity-dependent neural differentiation of pluripotent stem cells |
| title_short | Imaging-based chemical screening reveals activity-dependent neural differentiation of pluripotent stem cells |
| title_sort | imaging based chemical screening reveals activity dependent neural differentiation of pluripotent stem cells |
| topic | chemical genetic small molecule tool cellular differentiation dopaminergic neuron pluripotent stem cell |
| url | https://elifesciences.org/articles/00508 |
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