Dynamic Ligand Discrimination in the Notch Signaling Pathway

Abstract

The Notch signaling pathway comprises multiple ligands that are used in distinct biological contexts. In principle, different ligands could activate distinct target programs in signal-receiving cells, but it is unclear how such ligand discrimination could occur. Here, we show that cells use dynamics to discriminate signaling by the ligands Dll1 and Dll4 through the Notch1 receptor. Quantitative single-cell imaging revealed that Dll1 activates Notch1 in discrete, frequency-modulated pulses that specifically upregulate the Notch target gene Hes1. By contrast, Dll4 activates Notch1 in a sustained, amplitude-modulated manner that predominantly upregulates Hey1 and HeyL. Ectopic expression of Dll1 or Dll4 in chick neural crest produced opposite effects on myogenic differentiation, showing that ligand discrimination can occur in vivo. Finally, analysis of chimeric ligands suggests that ligand-receptor clustering underlies dynamic encoding of ligand identity. The ability of the pathway to utilize ligands as distinct communication channels has implications for diverse Notch-dependent processes.

Optogenetic inhibition of Delta reveals digital Notch signalling output during tissue differentiation

“…Moreover, once cleaved, NICD molecules move into the nucleus within minutes [4]. While several studies have focused on the mechanisms controlling Notch activation by ligand endocytosis [5][6][7][8][9], knowledge about the activation of Notch targets by cleaved NICD and the dynamics involved remains limited [10][11][12][13][14]. More broadly, the role of signal dynamics in controlling developmental processes and tissue differentiation is only partially understood [15][16][17][18][19].…”

Decoding the Notch signal

“…in both organisms depending on the context(Figure 2b). Bursts of Notch target gene transcription in the order of hours have also been observed in cultured cell models(Nandagopal et al, 2018), but whether this represents bursts at the promoter level or it is also the result of feedback regulation remains unclear.Regardless of whether the time scale of transcriptional bursting is minutes or hours, binding of CSL-NICD complexes to target enhancers appears to occur over a range that is at least an order of magnitude faster. However, this is thought to be a consequence of genetic feedback rather than the bursting behavior of a single gene.…”

Overlapping but distinct roles for NOTCH receptors in human cardiovascular disease

“…Recent work has showed that 2 ligands of the Notch receptor (Dll1 and Dll4) are able to activate distinct targets through the same Notch receptor. This discrimination is made based upon activation dynamics, whereby Dll1 induces a pulsed Notch activation and Dll4 induces a sustained activation . Therefore, activation dynamics adds an extra layer of complexity to the Notch pathway and could be important in the development of distinct phenotypes.…”