Dynamic Ligand Discrimination in the Notch Signaling Pathway

Nagarajan Nandagopal, Leah A. Santat, Lauren LeBon, David Sprinzak, Marianne E. Bronner, Michael B. Elowitz*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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. Notch ligands activate distinct targets through the same Notch receptor by triggering pulsatile or sustained activation dynamics.

Original languageEnglish
Pages (from-to)869-880.e19
Issue number4
StatePublished - 8 Feb 2018


FundersFunder number
National Science FoundationEFRI 1137269
National Institutes of Health
National Institute of Child Health and Human DevelopmentR01HD075335
Defense Advanced Research Projects AgencyHR0011-16-0138
National Stroke Foundation


    • Notch pathway
    • intercellular signaling
    • ligand multiplicity
    • myogenesis
    • signal decoding
    • signal encoding
    • signaling dynamics
    • single cell dynamics
    • systems biology


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