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ANR funded project

(DS0402) 2016
Projet ENTEROCYTE_PURGE_RECOVERY

Toxin and xenobiotics-inuced purge and subsequent recovery of enterocytes

The intestine is a critical interface with the environment. By feeding, animals get exposed to toxins or toxicants contaminating nutrients. We have discovered a novel stress response of Drosophila enterocytes: pore-forming toxin or xenobiotics such as caffeine, metallic ions, or paraquat trigger a limited extrusion of apical cytoplasm and damaged organelles, possibly along with the toxicant, thus yielding a homogenously thin intestinal epithelium. There is no increased enterocyte cell death in the process. The enterocytes then recover their original shape and volume in 6-9 hours by a noncell-autonomous process. This response protects enterocytes from occasional intoxications from microbial or environmental origin present in contaminated food. This protective response thus involves two distinct phases. First occurs a limited extrusion of cytoplasm that does not lyse it, the purge; next, a recovery phase takes place allowing the intestinal epithelium to regain its original thickness and morphology.
We have identified the induction of several secreted peptide-coding genes named "what else" by a pore-forming toxin, hemolysin, secreted by the entomopathogenic bacterium Serratia marcescens. Their expression requires a cyclin of rather undefined function, which does not involve a cell cycle role in mature enterocytes. Interestingly, what else genes ectopic expression compensates the cyclin mutant phenotype, i.e., an intestinal epithelium that remains thin for lack of recovery phase. This ectopic expression of what else genes also recapitulates another property of the system: a prior exposure to hemolysin or to some xenobiotics primes the intestinal epithelium against a secondary exposure to hemolysin, a Sm virulence factor. Thus, What else factors account for the noncell-autonomous properties of the recovery phase. We have identified through combined genetic and transcriptomics approaches about 100 genes potentially required for the recovery phase.
A first aim of our project shall consist in studying how what else genes expression is regulated. Thus, we shall study on the one hand a putative transcription factor that binds to the cyclin and on the other hand a signal transduction pathway that may be initiated by mitochondria, which are strongly affected prior to the cytoplasmic purge.
We shall determine in a second objective how a developmental regulator makes enterocytes competent for the recovery phase induced by hemolysin or xenobiotics, either to initiate what else genes expression or further downstream in the enterocytes induced by these secreted peptides.
A third goal will be to understand how recovery occurs from a metabolic standpoint. We hypothesize that there is an inversion of normal metabolic fluxes, from organs and tissues back to the intestine. Once this point will have been demonstrated, we shall focus on an amino-acid transporter that may also regulate a major cellular growth pathway.
Our preliminary data show that human enterocyte cell cultures that form epithelia, as well as the mouse intestinal epithelium in vivo, also undergoes epithelial thinning and subsequent rapid recovery upon exposure to Sm hemolysin. Thus, enterocyte purge coupled to fast recovery may be evolutionarily conserved, a hypothesis we shall attempt to validate, first in cultured epithelia and then in vivo. Next, we shall test whether exposure to xenobiotics also triggers the purge of mammalian enterocytes in culture and in vivo.

Partners

ICS Institut Clinique de la Souris

IGBMC Institut de Génétique et de Biologie Moléculaire et Cellulaire

RIDI Réponse immunitaire et Développement chez les Insectes

ANR grant: 479 544 euros
Beginning and duration: octobre 2016 - 42 mois

 

ANR Programme: (DS0402) 2016

Project ID: ANR-16-CE13-0011

Project coordinator:
Monsieur Dominique FERRANDON (Réponse immunitaire et Développement chez les Insectes)

 

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The project coordinator is the author of this abstract and is therefore responsible for the content of the summary. The ANR disclaims all responsibility in connection with its content.