Salvador\u2013Warts\u2013Hippo pathway regulates sensory organ development via caspase-dependent nonapoptotic signaling

Lan-Hsin Wang,Nicholas E Baker

doi:10.1038/s41419-019-1924-3

Abstract

The fundamental roles for the Salvador–Warts–Hippo (SWH) pathway are widely characterized in growth regulation and organ size control. However, the function of SWH pathway is less known in cell fate determination. Here we uncover a novel role of the SWH signaling pathway in determination of cell fate during neural precursor (sensory organ precursor, SOP) development. Inactivation of the SWH pathway in SOP of the wing imaginal discs affects caspase-dependent bristle patterning in an apoptosis-independent process. Such nonapoptotic functions of caspases have been implicated in inflammation, proliferation, cellular remodeling, and cell fate determination. Our data indicate an effect on the Wingless (Wg)/Wnt pathway. Previously, caspases were proposed to cleave and activate a negative regulator of Wg/Wnt signaling, Shaggy (Sgg)/GSK3β. Surprisingly, we found that a noncleavable form of Sgg encoded from the endogenous locus after CRISPR-Cas9 modification supported almost normal bristle patterning, indicating that Sgg might not be the main target of the caspase-dependent nonapoptotic process. Collectively, our results outline a new function of SWH signaling that crosstalks to caspase-dependent nonapoptotic signaling and Wg/Wnt signaling in neural precursor development, which might be implicated in neuronal pathogenesis.

Highlights

Introduction The SalvadorWarts–Hippo (SWH) pathway has been recognized as a significant regulator for growth control, tissue regeneration, and stem cell pluripotency[1,2]
By studying how ex takes part in sensory organ precursor (SOP) development, we discovered a crosstalk between SWH pathway and caspase-dependent nonapoptotic signaling mediated through Wg pathway
The Notch pathway has been shown to play important role in bristle development[40], E(spl) expression was not changed when ex was mutated (Supplementary Fig. 3), consistent with previous conclusions that ex mutations do not reduce Notch signaling[41]. These results suggest that Wg signaling pathway acts downstream of ex in SOP cell formation, and that the SWH pathway may by the source of the nonapoptotic caspase activity that acts on Wg signaling

Summary

Introduction

Introduction The SalvadorWarts–Hippo (SWH) pathway has been recognized as a significant regulator for growth control, tissue regeneration, and stem cell pluripotency[1,2]. The regulation of SWH pathway depends on its response to various upstream stimuli through intercellular junctions, including adhesion cues. Official journal of the Cell Death Differentiation Association. Wang and Baker Cell Death and Disease (2019)10:669 transcriptional activity of Yki/YAP/TAZ through nuclear export, cytoplasmic retention, and protein degradation[8,9,10]. In addition to intrinsically regulates Yki activity, Ex, as an apical junctions-localized protein, transduces signaling cues through binding to the apical membrane protein Crumbs (Crb, CRB3 in mammals)[13,14,15,16]. It has been demonstrated that activation of the SWH pathway through elevating expanded (ex) levels is required to eliminate the inappropriately differentiating neurons during development[18,19]. Whether SWH pathway has any roles in normal neurogenesis remained unclear

Methods

Results

Conclusion