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We use early zebrafish development as a readout of potential Wnt/b-catenin inhibitors. By activating the pathway at the level of GSK3 at 5 hours post fertilization, we seek inhibitors that act at the level of, or below, the b-catenin destruction complex. The entire assay is completed in 24 hours. In addition to identifying Wnt/b-catenin inhibitors we also simultaneously screen for toxicity and potential off target developmental defects.
About
Wnt signaling is involved in many aspects of development and in the maintenance of stem cells in the adult. Mutations in the Wnt/b-catenin destruction complex account for the initiation of over 90% of colorectal cancers. Targeting the cancer stem cell activated by Wnt is critical for effective therapeutics and current screening methods are ineffective at capturing the complexity of in vivo Wnt signaling. Thus, we have developed a robust in vivo model that recapitulates the inactivation of the destruction complex that results in an eyeless phenotype at 1 day of development. We use this model to screen for molecules that act at the level of, or downstream of, the destruction complex to inhibit b-catenin signaling and effectively restore the phenotype back to wild type. Importantly, our screen can differentiate between rescuing the eye (desired) from complete inhibition of Wnt signaling (undersirable) by observing other aspects of development such as neural patterning and heart development or using a transgenic Wnt reporter zebrafish line.
Key Benefits
Identifying "realistic" candidates for the therapeutic treatment of Wnt/b-catenin induced malignancies.
Applications
Drug screening