Wallenda regulates JNK-mediated cell death in Drosophila.

X Ma,W Li,Y Yang,D Zhang,W Xu,L Xue

doi:10.1038/cddis.2015.111

Abstract

The c-Jun N-terminal kinase (JNK) pathway plays essential roles in regulating a variety of cellular processes including proliferation, migration and survival. Previous genetic studies in Drosophila have identified numerous cell death regulating genes, providing new insights into the mechanisms for related diseases. Despite the known role of the small GTPase Rac1 in regulating cell death, the downstream components and underlying mechanism remain largely elusive. Here, we show that Rac1 promotes JNK-dependent cell death through Wallenda (Wnd). In addition, we find that Wnd triggers JNK activation and cell death via its kinase domain. Moreover, we show that both MKK4 and Hep are critical for Wnd-induced cell death. Furthermore, Wnd is essential for ectopic Egr- or Rho1-induced JNK activation and cell death. Finally, Wnd is physiologically required for loss of scribble-induced JNK-dependent cell death. Thus, our data suggest that wnd encodes a novel essential cell death regulator in Drosophila.

Highlights

Drosophila melanogaster, with its well-established genetic techniques and compact genome size, has been regarded as an excellent model organism to study PCD and its related signaling pathways.[3,4] The c-Jun N-terminal kinase (JNK)
Consistent with previous results that overexpression of the small GTPase Rac[1] would affect eye development,[7,14] we found that expression of Rac[1] under GMR promoter produced a complete eye loss phenotype (Figure 1b), resulting from extensive cell death posterior to the morphogenetic furrow (MF) in third instar eye discs (Figure 2f), as shown by acridine orange (AO) staining, a dye used to detect dying cells.[15]
We found GMR4Rac1-induced no-eye phenotype was slightly suppressed by knocking down mekk[1], Ask[1] or slpr (Figures 1j and l), but remained unaffected by expressing a dominant negative form of dTAK1 or mutation in dTAK1 (Figures 1h and i), suggesting dTAK1 is dispensable for Rac1-triggered cell death

Summary

Introduction

Drosophila melanogaster, with its well-established genetic techniques and compact genome size, has been regarded as an excellent model organism to study PCD and its related signaling pathways.[3,4] The c-Jun N-terminal kinase (JNK). Signaling has been implicated as one of the most important pathways that regulates various fundamental cell behaviors, such as proliferation, migration and cell death.[5,6]. By using Drosophila compound eye as a model, we found Rac[1] expression induces JNK-dependent cell death and identified Wallenda (Wnd), a MAPKKK (mitogen-activated protein kinase kinase kinase) member as an essential downstream mediator. We established Wnd as a general modulator of cell death in Drosophila by showing that it is required for ectopic Egr or Rho[1] and loss of Scribble (Scrib)-induced cell death

Methods

Results

Conclusion