Fringe proteins modulate Notch-ligand cis and trans interactions to specify signaling states.

Lauren Lebon,Hamed Jafar-Nejad,David Sprinzak,Michael B Elowitz,Tom V Lee

doi:10.7554/elife.02950

Abstract

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.

Highlights

The Notch signaling pathway mediates communication between adjacent cells (Artavanis-Tsakonas et al, 1999)
Notch signaling occurs when a DSL (Delta/Serrate/Lag2) ligand binds to a Notch receptor on a neighboring cell, triggering proteolytic cleavage of the Notch receptor and endocytosis of the Notch extracellular domain into the signal-sending cell (Fortini, 2009)
Overexpression and loss of function studies have revealed that DSL ligands can cis-inhibit the ability of a cell to receive a Notch signal, and that this effect depends on the interaction of the extracellular domains of the receptors and ligands in the same cell (Jacobsen et al, 1998; D'Souza et al, 2008)

Summary

Introduction

The Notch signaling pathway mediates communication between adjacent cells (Artavanis-Tsakonas et al, 1999). Notch signaling occurs when a DSL (Delta/Serrate/Lag2) ligand binds to a Notch receptor on a neighboring cell, triggering proteolytic cleavage of the Notch receptor and endocytosis of the Notch extracellular domain into the signal-sending cell (Fortini, 2009). This mechanism releases the Notch intracellular domain (NICD), which translocates to the nucleus and interacts with the CSL complex (CBF1/Suppressor of Hairless/Lag; known as RBP-Jκ) to initiate transcription of target genes (Artavanis-Tsakonas et al, 1999; Fortini, 2009).

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Results

Conclusion