Fringe proteins modulate Notch-ligand cis and trans interactions to specify signaling states
The Notch signaling pathway consists of multiple types of receptors and ligands, whose interactions can be tuned by Fringe glycosyltransferases. A major challenge is to determine how these components control the specificity and directionality of Notch signaling in developmental contexts. Here, we analyzed same-cell (cis) Notch-ligand interactions for Notch1, Dll1, and Jag1, and their dependence on Fringe protein expression in mammalian cells. We found that Dll1 and Jag1 can cis-inhibit Notch1, and Fringe proteins modulate these interactions in a way that parallels their effects on trans interactions. Fringe similarly modulated Notch-ligand cis interactions during Drosophila development. Based on these and previously identified interactions, we show how the design of the Notch signaling pathway leads to a restricted repertoire of signaling states that promote heterotypic signaling between distinct cell types, providing insight into the design principles of the Notch signaling system, and the specific developmental process of Drosophila dorsal-ventral boundary formation.
Additional Information© 2014 LeBon et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited. Received: 06 April 2014; Accepted: 31 August 2014; Published: 25 September 2014. This work was supported by the Gordon and Betty Moore Foundation through Grant GBMF2809 to the Caltech Programmable Molecular Technology Initiative; the National Science Foundation under Grant No. EFRI 1137269 and The NIH under grant R01 HD705335. We also acknowledge support from the NIH/NIGMS (R01GM084135 to HJN) and the March of Dimes Foundation (#1-FY10-501 to HJN). We thank Pulin Li, Joseph Markson, Sandy Nandagopal, Amit Lakhanpal, Emily Capra, Fangyuan Ding, and Leah Santat for technical assistance, as well as discussions and comments, Gerry Weinmaster for helpful comments on the manuscript, Yi-Dong Li and Jessica Leonardi for assistance with the generation of transgenic flies, and Robert Fleming, Shinya Yamamoto, and The Bloomington Drosophila Stock Center for fly strains. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. Author contributions: LL, TVL, DS, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article; HJ-N, MBE, Conception and design, Analysis and interpretation of data, Drafting or revising the article.
ErrataCorrection: Hamed Jafar-Nejad and David Sprinzak were incorrectly listed as third and fourth authors respectively. The correct author order is: Lauren LeBon, Tom V Lee, David Sprinzak, Hamed Jafar-Nejad and Michael B Elowitz.
Supplemental Material - supplementary-file-1.media-3.docx