A high-throughput screen for Wnt/β-catenin signaling pathway modulators in human iPSC-derived neural progenitors

J Biomol Screen. 2012 Oct;17(9):1252-63. doi: 10.1177/1087057112456876. Epub 2012 Aug 24.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Glycogen Synthase Kinase 3 / antagonists & inhibitors
  • High-Throughput Screening Assays / methods*
  • Humans
  • Induced Pluripotent Stem Cells / cytology
  • Induced Pluripotent Stem Cells / metabolism
  • Lithium / pharmacology
  • Mental Disorders / drug therapy
  • Mental Disorders / metabolism
  • Neural Stem Cells / cytology
  • Neural Stem Cells / drug effects*
  • Neural Stem Cells / metabolism
  • Reproducibility of Results
  • Small Molecule Libraries / pharmacology
  • Wnt Signaling Pathway / drug effects*
  • Wnt3A Protein / metabolism
  • beta Catenin / metabolism


  • Small Molecule Libraries
  • Wnt3A Protein
  • beta Catenin
  • Lithium
  • Glycogen Synthase Kinase 3