Cis-activation in the Notch signaling pathway

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Abstract

The Notch signaling pathway consists of transmembrane ligands and receptors that can interact both within the same cell (cis) and across cell boundaries (trans). Previous work has shown that cis-interactions act to inhibit productive signaling. Here, by analyzing Notch activation in single cells while controlling cell density and ligand expression level, we show that cis-ligands can also activate Notch receptors. This cis-activation process resembles trans-activation in its ligand level dependence, susceptibility to cis-inhibition, and sensitivity to Fringe modification. Cis-activation occurred for multiple ligand-receptor pairs, in diverse cell types, and affected survival in neural stem cells. Finally, mathematical modeling shows how cis-activation could potentially expand the capabilities of Notch signaling, for example enabling 'negative' (repressive) signaling. These results establish cis-activation as an additional mode of signaling in the Notch pathway, and should contribute to a more complete understanding of how Notch signaling functions in developmental, physiological, and biomedical contexts.

Data availability

RNA sequencing data have been deposited in GEO under accession codes GSE113937. Source data files have been provided for Figure 5.

The following data sets were generated

(2018) Gene expression in cultured mouse neural progenitor cells
NCBI Gene Expression Omnibus, GSE113937.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE113937

Article and author information

Author details

Nagarajan Nandagopal

Division of Biology and Biological Engineering, Howard Hughes Medical Institute, California Institute of Technology, Pasadena, United States

Competing interests
The authors declare that no competing interests exist.
Leah A Santat

Division of Biology and Biological Engineering, Howard Hughes Medical Institute, California Institute of Technology, Pasadena, United States

Competing interests
The authors declare that no competing interests exist.
Michael B Elowitz

Division of Biology and Biological Engineering, Howard Hughes Medical Institute, California Institute of Technology, Pasadena, United States

For correspondence
melowitz@caltech.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-1221-0967

Funding

National Institutes of Health (R01 HD075335)

Nagarajan Nandagopal
Leah A Santat
Michael B Elowitz

Howard Hughes Medical Institute (M.B.E.)

Nagarajan Nandagopal
Leah A Santat
Michael B Elowitz

Defense Sciences Office, DARPA (HR0011-16-0138)

Nagarajan Nandagopal
Leah A Santat
Michael B Elowitz

National Science Foundation (EFRI 1137269)

Nagarajan Nandagopal
Leah A Santat
Michael B Elowitz

Howard Hughes Medical Institute (Graduate Student Fellowship)

Nagarajan Nandagopal

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.