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02465 am a22002533u 4500 |
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92893 |
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|a dc
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|a Zhao, Wen-Ning
|e author
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|a Picower Institute for Learning and Memory
|e contributor
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|a Tsai, Li-Huei
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|a Cheng, Chialin
|e author
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|a Theriault, Kraig M.
|e author
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|a Sheridan, Steven D.
|e author
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|a Tsai, Li-Huei
|e author
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|a Haggarty, Stephen J.
|e author
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|a A High-Throughput Screen for Wnt/β-Catenin Signaling Pathway Modulators in Human iPSC-Derived Neural Progenitors
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|b Sage Publications,
|c 2015-01-15T18:40:55Z.
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|z Get fulltext
|u http://hdl.handle.net/1721.1/92893
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|a Wnt/β-catenin signaling has emerged as a central player in pathways implicated in the pathophysiology and treatment of neuropsychiatric disorders. To identify potential novel therapeutics for these disorders, high-throughput screening (HTS) assays reporting on Wnt/β-catenin signaling in disease-relevant contexts are needed. The use of human patient-derived induced pluripotent stem cell (iPSC) models provides ideal disease-relevant context if these stem cell cultures can be adapted for HTS-compatible formats. Here, we describe a sensitive, HTS-compatible Wnt/β-catenin signaling reporter system generated in homogeneous, expandable neural progenitor cells (NPCs) derived from human iPSCs. We validated this system by demonstrating dose-responsive stimulation by several known Wnt/β-catenin signaling pathway modulators, including Wnt3a, a glycogen synthase kinase-3 (GSK3) inhibitor, and the bipolar disorder therapeutic lithium. These responses were robust and reproducible over time across many repeated assays. We then conducted a screen of ~1500 compounds from a library of Food and Drug Administration-approved drugs and known bioactives and confirmed the HTS hits, revealing multiple chemical and biological classes of novel small-molecule probes of Wnt/β-catenin signaling. Generating these type of pathway-selective, cell-based phenotypic assays in human iPSC-derived neural cells will advance the field of human experimental neurobiology toward the goal of identifying and validating targets for neuropsychiatric disorders.
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|a National Institute of Mental Health (U.S.) (Grant R01MH091115)
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|a Stanley Medical Research Institute
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| 546 |
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|a en_US
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|a Article
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|t Journal of Biomolecular Screening
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