Unidirectional Notch signaling depends on continuous cleavage of Delta

Amir Sapir,Rachel Tsruya,Ben-Zion Shilo,Efrat Assa-Kunik,Eyal Schejter

doi:10.1242/dev.01546

Abstract

Unidirectional signaling from cells expressing Delta (Dl) to cells expressing Notch is a key feature of many developmental processes. We demonstrate that the Drosophila ADAM metalloprotease Kuzbanian-like (Kul) plays a key role in promoting this asymmetry. Kul cleaves Dl efficiently both in cell culture and in flies, and has previously been shown not to be necessary for Notch processing during signaling. In the absence of Kul in the developing wing, the level of Dl in cells that normally receive the signal is elevated, and subsequent alterations in the directionality of Notch signaling lead to prominent phenotypic defects. Proteolytic cleavage of Dl by Kul represents a general mechanism for refining and maintaining the asymmetric distribution of Dl, in cases where transcriptional repression of Dl expression does not suffice to eliminate Dl protein.

Highlights

The Notch signaling pathway serves as one of the cardinal means by which distinct fates are induced in adjacent cells during development
ADAM proteins have a characteristic domain signature, including a signal peptide followed by a pro-domain, a metalloprotease domain possessing a zinc-binding catalytic pocket, and a disintegrin domain
Among the five Drosophila metalloproteases, a single homolog was identified for TNF-α converting enzyme (TACE), two homologs were found for Meltrin-α, and two for ADAM10

Summary

Introduction

The Notch signaling pathway serves as one of the cardinal means by which distinct fates are induced in adjacent cells during development. This is achieved by presentation of the ligands Delta (Dl) or Serrate (Ser) on the cell surface of the sending cell, and activation of the Notch receptor in the receiving cells. Given the transmembrane nature of the ligands, activation is executed only in cases of direct contact between the cells. A sharp distinction between the sending and receiving cells is essential, because signaling is carried out only between neighboring cells. Activation of Notch in the adjacent (signal-receiving) cells leads to a reduction in Dl levels (Heitzler et al, 1996)

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