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Published February 8, 2018 | Accepted Version + Published + Supplemental Material
Journal Article Open

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 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.

Additional Information

© 2018 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Open Access funded by the US Department of Defense (DoD) or performed by an employee of DoD. Available online 1 February 2018. Author Contributions: Conceptualization, N.N. and M.B.E.; Methodology, N.N. and M.B.E.; Investigation, N.N. and L.A.S.; Resources, L.L.B. and M.E.B.; Writing – Original Draft, N.N. and M.B.E.; Writing – Review & Editing, N.N., L.A.S., D.S., M.E.B., and M.B.E.; Visualization, N.N., D.S., an d M.B.E.; Supervision and Funding Acquisition, M.B.E. We thank Mark Budde, Joe Markson, Pulin Li, Yihan Lin, James Linton, Emily Capra, Jordi Garcia-Ojalvo, and Xiaojing Gao for critical feedback on the manuscript, and Young-Wook Jun, Roy Kishony, Irv Bernstein, Stephen Blacklow, and Elizabeth Jensen for helpful discussions. Harry Choi and Colby Calvert, Caltech Flow Cytometry Facility, Caltech Biological Imaging Facility, and the Millard and Muriel Jacobs Genetics and Genomics Laboratory at Caltech provided essential technical assistance. This work was supported by the Defense Advanced Research Projects Agency (HR0011-16-0138), by the NIH (R01 HD075335), and the NSF (EFRI 1137269). N.N. was a Howard Hughes Medical Institute International Student Research fellow. The authors declare no competing interests.

Attached Files

Published - 1-s2.0-S0092867418300023-main.pdf

Accepted Version - nihms-999667.pdf

Supplemental Material - mmc1.pdf

Supplemental Material - mmc2.mp4

Supplemental Material - mmc3.mp4

Supplemental Material - mmc4.mp4

Supplemental Material - mmc5.mp4

Supplemental Material - mmc6.mp4


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August 21, 2023
October 18, 2023