EGF signal propagation during C. elegans vulval development mediated by ROM-1 rhomboid.

Amit Dutt,Stefano Canevascini,Erika Froehli-Hoier,Alex Hajnal,Julie Ahringer Julie Ahringer

doi:10.1371/journal.pbio.0020334

Abstract

During Caenorhabditis elegans vulval development, the anchor cell (AC) in the somatic gonad secretes an epidermal growth factor (EGF) to activate the EGF receptor (EGFR) signaling pathway in the adjacent vulval precursor cells (VPCs). The inductive AC signal specifies the vulval fates of the three proximal VPCs P5.p, P6.p, and P7.p. The C. elegans Rhomboid homolog ROM-1 increases the range of EGF, allowing the inductive signal to reach the distal VPCs P3.p, P4.p and P8.p, which are further away from the AC. Surprisingly, ROM-1 functions in the signal-receiving VPCs rather than the signal-sending AC. This observation led to the discovery of an AC–independent activity of EGF in the VPCs that promotes vulval cell fate specification and depends on ROM-1. Of the two previously reported EGF splice variants, the longer one requires ROM-1 for its activity, while the shorter form acts independently of ROM-1. We present a model in which ROM-1 relays the inductive AC signal from the proximal to the distal VPCs by allowing the secretion of the LIN-3L splice variant. These results indicate that, in spite of their structural diversity, Rhomboid proteins play a conserved role in activating EGFR signaling in C. elegans, Drosophila, and possibly also in mammals.

Highlights

Intercellular signaling pathways control many diverse processes, such as cell proliferation, differentiation, survival, migration, shape changes, and responses to the environment
EGF receptor (EGFR) ligands of the transforming growth factor-a (TGF-a) family are produced as membrane-tethered precursor proteins with a single extracellular epidermal growth factor (EGF) repeat that is cleaved off the membrane anchor (Pandiella and Massague 1991; Bosenberg et al 1993)
Five Rhomboid-Like Proteins in C. elegans Since the LIN-3 EGF growth factor is produced as a transmembrane precursor protein (Hill and Sternberg 1992), we asked whether an intramembrane serine protease of the Rhomboid family is involved in the proteolytic processing of LIN-3 EGF

Summary

Introduction

Intercellular signaling pathways control many diverse processes, such as cell proliferation, differentiation, survival, migration, shape changes, and responses to the environment. Growth factor peptides are often produced as inactive precursors that need to be processed before they can be released and activate their cognate receptors on the signalreceiving cells (Arribas et al 1996). EGFR ligands of the transforming growth factor-a (TGF-a) family are produced as membrane-tethered precursor proteins with a single extracellular EGF repeat that is cleaved off the membrane anchor (Pandiella and Massague 1991; Bosenberg et al 1993). Genetic analysis of Drosophila EGFR signaling has identified Rhomboid-1 as a protein necessary for Spitz activation in the signal-sending cell (Bier et al 1990; Golembo et al 1996; Guichard et al 2000; Wasserman et al 2000).

Methods

Results

Conclusion