Dynamic Ligand Discrimination in the Notch Signaling Pathway

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...

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Bibliographic Details
Published in:Cell 2018-02, Vol.172 (4), p.869-880.e19
Main Authors: Nandagopal, Nagarajan, Santat, Leah A., LeBon, Lauren, Sprinzak, David, Bronner, Marianne E., Elowitz, Michael B.
Format: Article
Language:English
Subjects:
Adaptor Proteins, Signal Transducing
Animals
Basic Helix-Loop-Helix Transcription Factors - biosynthesis
Basic Helix-Loop-Helix Transcription Factors - genetics
Calcium-Binding Proteins
Cell Cycle Proteins - biosynthesis
Cell Cycle Proteins - genetics
Chick Embryo
CHO Cells
Cricetulus
Humans
intercellular signaling
Intercellular Signaling Peptides and Proteins - genetics
Intercellular Signaling Peptides and Proteins - metabolism
Intracellular Signaling Peptides and Proteins - genetics
Intracellular Signaling Peptides and Proteins - metabolism
ligand multiplicity
Ligands
Membrane Proteins - genetics
Membrane Proteins - metabolism
Mice
myogenesis
Notch pathway
Receptor, Notch1 - genetics
Receptor, Notch1 - metabolism
Repressor Proteins - biosynthesis
Repressor Proteins - genetics
signal decoding
signal encoding
Signal Transduction
signaling dynamics
single cell dynamics
systems biology
Up-Regulation
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Description
Summary: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. [Display omitted] •Dll1 and Dll4 can activate distinct targets through the same Notch receptor•Ligand identity is encoded in pulsatile or sustained Notch activation dynamics•Dynamic encoding involves ligand-receptor clustering•Dll1 and Dll4 induce opposite cell fates during embryonic myogenesis Notch ligands activate distinct targets through the same Notch receptor by triggering pulsatile or sustained activation dynamics.
ISSN:0092-8674
1097-4172
DOI:10.1016/j.cell.2018.01.002