Dll3 (light blue) inhibits Notch, resulting in neurogenesis (purple) in frog embryos.

Notch is activated by ligands on apposing cells. When expressed in the same cell as Notch, some DSL (Delta, Serrate, Lag2) ligands become inhibitors. On page 983, Ladi et al. show that Dll3 is the only known DSL ligand that is dedicated solely to Notch inactivation, leaving the job of activator behind.

Dll3 seems to be important for somitogenesis, as its loss disrupts somite patterning. But since cycles of Notch activity control somite formation, it has not been clear whether the important function of Dll3 is to turn Notch on or off. The new findings show that Dll3 must be turning down Notch signaling.

Unlike all other known DSL ligands, Dll3 was unable to activate Notch in apposing cells. In fact, Dll3 and Notch did not even interact unless they were in the same cell. When the authors examined the Dll3 structure, they found that most of the conserved activating regions of DSL ligands had been lost.

Notch is widely expressed in mammals, and the mechanism for turning on its pathway is rather simple—the receptor itself is also the signal transducer. Perhaps for this reason, says principal investigator Gerry Weinmaster, “several levels of negative regulation must be superimposed on its activation scheme to keep it under tight control. Notch seems to have more ways to turn off signaling than to turn it on.” The evolution of a dedicated Notch inhibitor that resembles its activators seems to be one more way to keep Notch in check.