A High-Throughput Screen for Wnt/β-Catenin Signaling Pathway Modulators in Human iPSC-Derived Neural Progenitors
Author(s)Zhao, Wen-Ning; Cheng, Chialin; Theriault, Kraig M.; Sheridan, Steven D.; Tsai, Li-Huei; Haggarty, Stephen J.; ... Show more Show less
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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.
DepartmentPicower Institute for Learning and Memory
Journal of Biomolecular Screening
Zhao, Wen-Ning, Chialin Cheng, Kraig M. Theriault, Steven D. Sheridan, Li-Huei Tsai, and Stephen J. Haggarty. “A High-Throughput Screen for Wnt/β-Catenin Signaling Pathway Modulators in Human iPSC-Derived Neural Progenitors.” Journal of Biomolecular Screening 17, no. 9 (August 24, 2012): 1252–1263.
Author's final manuscript