Loss-of-function screens are powerful tools for identifying gene contribution in a given biological context. Over the past decade, the RNA interference technology has become a dominant approach in the loss-of-function screen-based gene discovery1. However, about 3 quarters of genes in mammalian genomes belong to gene families and have functional redundant homologs. While this functional redundancy protects cells and organisms from deleterious mutations2, it also masks phenotypic outcomes, resulting in false-negatives in loss-of-function screens that target individual genes. However, all of reported loss-of-function screens have been designed to target individual genes and thus suffer from limitations of the false-negatives.

The Wnt-β-catenin pathway plays pivotal roles in embryogenesis as well as in adult tissue homeostasis. Aberrant Wnt-β-catenin signaling has been linked to a wide range of pathologies in humans, including cancer. Wnt3A, a prototypic canonical Wnt, initiates its signaling by binding to a Frizzled (Fz) family receptor and a low density lipoprotein-related protein (LRP) 5/6 coreceptor, causing, via the intracellular signaling protein dishevelled (Dvl), the stabilization and accumulation of β-catenin in both cytoplasm and nucleus by inhibiting the degradation function of destruction complex composed of GSK3, APC, Axin and β-TrCP. The nuclear β-catenin binds to the TCF family of transcription factors and regulates gene transcription3. Like other biological system, functional redundancy has been observed in the Wnt signaling pathway4,5,6. For instance, there are ten Fz (Fz1-10) and two LRP (LRP5/6), three Dvl (Dvl1-3), two GSK3 (GSK3α/β), two Axin (Axin1/2), and two β-TrCP (β-TrCP1/2).

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