Notch signaling

Notch signaling is a conserved juxtacrine pathway that governs cell-fate decisions, differentiation, and tissue homeostasis through direct cell-to-cell contact. Binding of Delta-like or Jagged ligands on signal-sending cells to Notch receptors (NOTCH1–4) on receiving cells triggers sequential proteolytic cleavages — first by ADAM metalloproteases (S2 cleavage), then by the γ-secretase complex (S3 cleavage) — releasing the Notch intracellular domain (NICD), which translocates to the nucleus and activates transcription via the CSL/RBPJ complex. Notch is a key regulator of satellite cell quiescence and muscle regeneration, neural progenitor specification, and T-cell development; its activity declines with age in multiple tissue compartments, impairing regenerative responses, and dysregulation in either direction — gain or loss of function — is associated with pathological ageing phenotypes and cancer.