Uif, a Large Transmembrane Protein with EGF-Like Repeats, Can Antagonize Notch Signaling in Drosophila

Gengqiang Xie,Qinglei Huang,Jun Ma,Renjie Jiao,Xuehong Liang,Hongtao Zhang,Guiping Du,Edward Giniger

doi:10.1371/journal.pone.0036362

Abstract

BackgroundNotch signaling is a highly conserved pathway in multi-cellular organisms ranging from flies to humans. It controls a variety of developmental processes by stimulating the expression of its target genes in a highly specific manner both spatially and temporally. The diversity, specificity and sensitivity of the Notch signaling output are regulated at distinct levels, particularly at the level of ligand-receptor interactions.Methodology/Principal FindingsHere, we report that the Drosophila gene uninflatable (uif), which encodes a large transmembrane protein with eighteen EGF-like repeats in its extracellular domain, can antagonize the canonical Notch signaling pathway. Overexpression of Uif or ectopic expression of a neomorphic form of Uif, Uif*, causes Notch signaling defects in both the wing and the sensory organ precursors. Further experiments suggest that ectopic expression of Uif* inhibits Notch signaling in cis and acts at a step that is dependent on the extracellular domain of Notch. Our results suggest that Uif can alter the accessibility of the Notch extracellular domain to its ligands during Notch activation.Conclusions/SignificanceOur study shows that Uif can modulate Notch activity, illustrating the importance of a delicate regulation of this signaling pathway for normal patterning.

Highlights

Notch signaling is an evolutionarily conserved signaling pathway that regulates a variety of different developmental processes, including adult homeostasis and stem cell development [1,2,3,4]
Such an interaction induces two consecutive proteolytic processes that result in the release of the Notch intracellular domain, which is translocated to the nucleus and activates transcription of its target genes by interacting with the DNA-binding protein Suppressor of Hairless (Su(H)) and the coactivator Mastermind
Expression of Uif* driven by A9-Gal4 and MS1096-Gal4 in the dorsal compartment of the wing led to thickened veins (Figure 1E and 1F). These results show that ectopic expression of Uif* causes patterning defects during development

Summary

Introduction

Notch signaling is an evolutionarily conserved signaling pathway that regulates a variety of different developmental processes, including adult homeostasis and stem cell development [1,2,3,4]. In Drosophila, both the Notch receptor and its canonical ligands, Delta (Dl) and Serrate (Ser), are transmembrane proteins with large extracellular domains consisting primarily of EGF-like repeats. The complexity of the biological processes controlled by the Notch signaling pathway requires precise regulation of its activity, at the level of ligandreceptor interactions. Crumbs (Crb), an EGF-like repeat-containing large transmembrane protein well characterized for its role in epithelial organization [10], was recently shown to act as a negative regulator of Notch signaling in the Drosophila wing [11]. Notch signaling is a highly conserved pathway in multi-cellular organisms ranging from flies to humans It controls a variety of developmental processes by stimulating the expression of its target genes in a highly specific manner both spatially and temporally. The diversity, specificity and sensitivity of the Notch signaling output are regulated at distinct levels, at the level of ligand-receptor interactions

Methods

Results

Conclusion