Venue : Centre Broca
Zoom: https://u-bordeaux-fr.zoom.us/j/89348045291?pwd=1XUpvyVHZelbp8QlRhJq58FithstuH.1
ID de réunion: 893 4804 5291
Code secret: 545344 
Fanny Hardet
Team : Purinergic mediated neuroinflammation and brain disorders
IMN
Title
Purinergic signaling pathway and mesodermal and neural differentiation during embryonic development
Abstract
The purinergic signaling pathway, involving purines, whose extracellular concentration is controlled by ectonucleotidases, as ligands for purinergic receptors P2 (P2X and P2Y) and P1 (AdorA), regulates the physiology of many organs in adult vertebrates, and its dysregulation is correlated with several human pathologies, degenerative or developmental in nature. Understanding its functions during embryonic development is essential to understanding the molecular mechanisms that are dysregulated in these pathologies. However, its embryonic roles in an in vivo context remain poorly understood.
The amphibian model Xenopus laevis, due to its biological characteristics and the various genetic tools available, is a model of choice for exploring the molecular mechanisms and signaling pathways that regulate embryogenesis.
Previous work by my team has shown that the kidney and nervous system are major sites of expression for the actors in this signaling pathway. Based on their expression profile, several enzymes and receptors were selected for functional studies.
The objective of my thesis was to study the embryonic roles of some of these actors, namely ectonucleotidases and P2X receptors. To do this, gain-of-function and loss-of-function experiments were used in combination with histological approaches to analyze the phenotypes induced at different embryonic stages, as well as electrophysiological and behavioral approaches. My work established that the ectonucleotidase ENTPD5 is necessary and sufficient for kidney formation. This capacity is dependent on the enzymatic activity of ENTPD5, its subcellular localization, and the cellular environment. ENTPD5 also regulates the expression of master genes involved in nephrogenesis. I have thus demonstrated the conservation of molecular mechanisms, which involve an ectonucleotidase from the ENTPDase family upstream of these networks. Furthermore, as part of an international collaboration, my work has demonstrated the deleterious effects of the loss of function of the ENPP6 ectonucleotidase and that certain mutations of this gene, identified in patients with renal pathologies (CAKUT), alter the development of the pronephros. We have also characterized the in vitro electrophysiological properties of exogenous Xenopus P2X receptors in order to elucidate their role in the formation of the sensory nervous system and in nociception, for which we have developed appropriate behavioral tests. Finally, we revealed that the P2X5 receptor, described as non-functional in humans, as well as the metabolic pathways of purine biosynthesis and recycling, are involved in the formation of somites and hypaxial muscles in Xenopus.
Thus, my thesis work highlights the implications of purinergic signaling during embryogenesis, improving our understanding of developmental mechanisms and paving the way for new potential therapeutic targets.
Key words
Embryogenesis, ectonucleotidases, P2X, xenopus, pronephros, muscles, sensory nervous system, nociception, electrophysiology
Publications
Jury
Mme BILLOTET Clotilde, Professeur, Université de Bordeaux, Présidente du jury
M. BELLEFROID Éric, Professeur, Université Libre de Bruxelles, Rapporteur
Mme LÉVI Sabine, Directrice de Recherche, ESPCI Paris, Rapportrice
M. AUGUSTE Patrick, Maître de Conférences, Université de Bordeaux, Examinateur
M. RIOU Jean-François, Chargé de recherche, IBPS Paris, Membre Invité