Notch signaling was first discovered in Drosophila melanogaster, where it is involved in cell lineage differentiation. Notch signaling regulates the maintenance and differentiation of intestinal stem cells or ISCs by controlling the expression of atonal homolog 1 or Atoh1. Atoh1 directs cells to differentiate into secretory cells.

Direct cell-to-cell contact is needed for the activation of Notch signaling. The signal is initiated when a notch ligand binds to a receptor on an adjacent cell, also known as trans-binding. In contrast, the signal is inhibited when the ligand binds to the same cell's receptor or cis-binding. During trans-activation, ADAM protease cleaves the extracellular region of the notch receptor, and γ-secretase cleaves the intracellular domain, also called the Notch intracellular domain (NICD), which translocates into the nucleus and activates the Hairy enhancer of split (Hes). Hes, in turn, inhibits Atoh1 and prevents Notch receptor cells from differentiating into secretory cells.

During tissue damage to the intestinal epithelium, the Paneth cells de-differentiate and replace the damaged cells via Notch signaling. Dysregulated Notch signals in the intestinal cells can cause various diseases. For example, mutations in Hes1 or Atoh1 can give rise to colorectal tumors. Reduced Notch signaling is linked to the rare inflammatory condition known as Celiac disease, which causes an allergic reaction when gluten is consumed. Therefore, targeting the Notch signaling pathway can be a therapeutic strategy for treating certain intestinal disorders.