Dynamic Ligand Discrimination in the Notch Signaling Pathway

Nagarajan Nandagopal; Leah A Santat; Lauren LeBon; David Sprinzak; Marianne E Bronner; Michael B Elowitz

doi:10.1016/j.cell.2018.01.002

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.

Authors

Nagarajan Nandagopal¹, Leah A Santat¹, Lauren LeBon², David Sprinzak³, Marianne E Bronner⁴, Michael B Elowitz⁵

Affiliations

¹ Howard Hughes Medical Institute and Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
² Calico Life Sciences, 1170 Veterans Boulevard, South San Francisco, CA 94080, USA.
³ Department of Biochemistry and Molecular Biology, Wise Faculty of Life Sciences, Tel-Aviv University, Tel Aviv, Israel.
⁴ Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
⁵ Howard Hughes Medical Institute, Division of Biology and Biological Engineering, Department of Applied Physics, California Institute of Technology, Pasadena, CA 91125, USA. Electronic address: melowitz@caltech.edu.

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

Adaptor Proteins, Signal Transducing
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

Adaptor Proteins, Signal Transducing
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

Abstract

Publication types

MeSH terms

Substances

Grants and funding