Projet ANR-12-BSV2-0010 – ShaPiShaPo : Mécanismes de régulation de la morphogenèse épitheliale chez la drosophile : étude de l’ubiquitine ligase E3 Neuralized
Programme : Blanc - SVSE 2 - Biologie cellulaire et biologie du développement (Blanc SVSE 2) 2012
Année de financement : 2012
Coordinateur du projet : Monsieur François SCHWEISGUTH (Institut Pasteur)
Partenaires : Institut Pasteur
Montant : 476632.0 euros
Date de début : 2013
Durée : 36 mois
Résumé : Epithelial tissues serve many functions, including secretion, selective absorption and protection of inner tissues from pathogens and damaging agents. Both selective exchange and barrier functions depend on the structure of epithelia that form continuous sheets of interconnected cells that are polarized along an apical-basal axis. Epithelia are dynamic structures that can undergo both rapid turnover and dynamic remodelling. Alterations in the structure and homeostasis of epithelial tissues have profound consequences in human health, notably in infection diseases and carcinomas. Thus, understanding how epithelial polarity is established and remodelled during morphogenesis is a major issue of both fundamental interest and medical relevance.
Genetic studies in model organisms have led to the identification of core polarity factors that regulate the establishment and dynamic remodelling of epithelia. In particular, the Drosophila embryo provides an outstanding model system to study epithelium formation and remodelling during morphogenesis. Our laboratory has recently identified a novel mechanism that regulates epithelial polarity in the early Drosophila embryo. This regulatory mechanism involves the inhibition of the conserved E3 ubiquitin ligase Neuralized by proteins of the Bearded family. Neuralized encodes a conserved E3 ubiquitin ligase whereas proteins of the Bearded family are small proteins that inhibit Neuralized by competing the Neuralized-substrate interactions. Neuralized and Bearded are so far only known for their activities as regulators of the endocytosis of Delta, the ligand for the Notch receptor. Of note, this function of Neuralized is not conserved in humans.
Our recent work showing that the E3 ubiquitin ligase Neuralized regulates epithelial morphogenesis in several contexts raise several interesting questions: what is the exact role of Neuralized during mesoderm invagination at gastrulation? what are the targets of the Bearded proteins during gastrulation? Does Neuralized regulate the epithelial remodelling of Sensory Organ Precursor cells (SOPs) that precedes asymmetric cell division? what is the mode of action of Neuralized in epithelial morphogenesis? Is the E3 ubiquitin ligase activity required for the regulatory activity of Neuralized? If so, does Neuralized regulate the endocytosis of an apical cargo? what is this cargo? More generally, what are the ubiquitination targets of Neuralized? The project described herein will address these specific questions.
In conclusion, this project will provide novel insights into the mechanistic basis of polarity remodelling during epithelial morphogenesis. Since the function of Neuralized in Delta signalling is not conserved in mammals, we suggest that the conserved function of Neuralized is in the one studied here for the first time. Thus, the novel mechanistic insights gained from our analysis of Neuralized in Drosophila may have important impact for our understanding of epithelial morphogenesis in humans.