Canonical Wnt signalling is critical for ISC niche maintenance and is potentiated by Lgr5.
In the absence of Wnt ligands, β-catenin is held in a destruction complex that includes Dvl, Axin, Ck1, Gsk3 and Apc which results in β-catenin being targeted to the proteasome for degradation (A). When present, canonical Wnt ligands (eg Wnt3a) bind to frizzled receptors (Fzd) on proliferation-permissible cells which then recruit LRP6 and Dvl and release β-catenin from the destruction complex allowing β-catenin stabilisation and cytoplasmic accumulation. β-catenin can then translocate to the nucleus and binds to the T-cell factor/lymphoid enhancer factor (Tcf/Lef) transcription factor which results in the activation of a panel of genes critical for cell division [110]. R-spondins (Rspo) are important in potentiating this pathway by binding to Lgr5 and recruiting the Rnf43 ubiquitin ligase which targets the Lgr5–Rspo–Rnf43 complex for lysosomal degradation thus preventing Rnf43 from removing Fzd from the cell membrane and stabilising Fzd to enhance its availability for Wnt ligands [62] (B).