Ets21c Governs Tissue Renewal, Stress Tolerance, and Aging in the Drosophila Intestine

Juliane Mundorf,Colin D Donohoe,Colin D Mcclure,Tony D Southall,Mirka Uhlirova

doi:10.1016/j.celrep.2019.05.025

Abstract

SummaryHomeostatic renewal and stress-related tissue regeneration rely on stem cell activity, which drives the replacement of damaged cells to maintain tissue integrity and function. The Jun N-terminal kinase (JNK) signaling pathway has been established as a critical regulator of tissue homeostasis both in intestinal stem cells (ISCs) and mature enterocytes (ECs), while its chronic activation has been linked to tissue degeneration and aging. Here, we show that JNK signaling requires the stress-inducible transcription factor Ets21c to promote tissue renewal in Drosophila. We demonstrate that Ets21c controls ISC proliferation as well as EC apoptosis through distinct sets of target genes that orchestrate cellular behaviors via intrinsic and non-autonomous signaling mechanisms. While its loss appears dispensable for development and prevents epithelial aging, ISCs and ECs demand Ets21c function to mount cellular responses to oxidative stress. Ets21c thus emerges as a vital regulator of proliferative homeostasis in the midgut and a determinant of the adult healthspan.

Highlights

The intestinal epithelium undergoes continuous homeostatic and acute, stress-induced cellular turnover to ensure tissue integrity and function throughout an organism’s lifetime
Ets21c Functions Downstream of Jun N-terminal kinase (JNK) Signaling in the Intestine The enhanced expression of ets21c in response to diverse stress signals (Blanco et al, 2010; Boutros et al, 2002; Broderick et al, 2014) and its established role downstream of JNK signaling in the Drosophila epithelial tumors (Ku€lshammer et al, 2015; Toggweiler et al, 2016) strongly suggest that it may mediate JNKinduced cellular responses in the adult fly intestine
The activation of JNK signaling in intestinal stem cells (ISCs)/EBs for 6 days resulted in the accumulation of esg+ cells and a marked distortion of the epithelial architecture (Figures 1D and S1B), as previously reported by Biteau et al (2008)

Summary

Introduction

The intestinal epithelium undergoes continuous homeostatic and acute, stress-induced cellular turnover to ensure tissue integrity and function throughout an organism’s lifetime. While primarily involved in nutrient resorption, the ECs serve as a physical and chemical barrier protecting the organism against toxins, pathogens, oxidative stress, and mechanical damage (Buchon et al, 2013). The runaway stem cell activity and loss of intestinal integrity due to chronic inflammation and increased stress load have been recognized as the prime underlying causes of aging-associated tissue decline and lifespan shortening (Biteau et al, 2008, 2010; Guo et al, 2014). How stress signals are transduced and integrated with the homeostatic maintenance mechanisms at the cellular level and the organ level is only partially understood

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Discussion

Conclusion