Figure 2.

Notch and Wnt signaling pathways. The differentiation of intestinal stem cells is mainly controlled by Notch and Wnt signaling pathways. The neighboring cells, including Paneth or stromal cells, provide Wnt proteins and R-spondins for activating Wnt signaling, and Notch ligands Dll1/4 for inhibiting Notch signaling. The canonical Wnt signaling is activated by the binding of Wnt protein binding to the LRP (Low density lipoprotein receptor-related protein)/Frizzled receptor complex to initiate the dissociation of intracellular APC complex and cause the release of β-catenin, which binds the transcriptional factor TCF and activates the expression of Atoh1 that controls intestinal stem cell differentiation. Lgr5 is an intestinal stem cell marker and an R-spondin ligand. The activation of Lgr5 also promotes the accumulation of β-catenin and causes the downstream activation [43]. Notch signaling is controlled by interactions of Notch and Dll1/4. The dissociation causes the cleavage of Notch receptor to release the NICD (notch intra-cellular domain), which is able to interact with other transcriptional factors to initiate the expression of Hes1 or Olfm4 for regulating stem cell differentiation in intestine [34].