Dynamic Ligand Discrimination in the Notch Signaling Pathway

Cell. 2018 Feb 8;172(4):869-880.e19. doi: 10.1016/j.cell.2018.01.002. Epub 2018 Feb 1.

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.

Keywords: Notch pathway; intercellular signaling; ligand multiplicity; myogenesis; signal decoding; signal encoding; signaling dynamics; single cell dynamics; systems biology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / biosynthesis
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • CHO Cells
  • Calcium-Binding Proteins
  • Cell Cycle Proteins / biosynthesis
  • Cell Cycle Proteins / genetics
  • Chick Embryo
  • Cricetulus
  • Humans
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Ligands
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Receptor, Notch1 / genetics
  • Receptor, Notch1 / metabolism*
  • Repressor Proteins / biosynthesis
  • Repressor Proteins / genetics
  • Signal Transduction*
  • Up-Regulation

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Calcium-Binding Proteins
  • Cell Cycle Proteins
  • DLK1 protein, human
  • DLL4 protein, human
  • DLL4 protein, mouse
  • Dlk1 protein, mouse
  • HEY1 protein, human
  • HEYL protein, human
  • Hey1 protein, mouse
  • Heyl protein, mouse
  • Intercellular Signaling Peptides and Proteins
  • Intracellular Signaling Peptides and Proteins
  • Ligands
  • Membrane Proteins
  • NOTCH1 protein, human
  • Notch1 protein, mouse
  • Receptor, Notch1
  • Repressor Proteins