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Evolution de la famille de gènes wnt, l’un des principaux activateurs des voies de signalisation Wnt, au cours du développement des métazoaires

Abstract : The Wnt signaling pathways play crucial roles during several processes of metazoan embryogenesis. For instance Wnt signaling is involved in morphogenetic movements as well as cell polarity and anteroposterior polarity establishment. Wnt signaling takes its name from the WNT proteins, which are secreted molecules that signal through their cognate receptors, the FRIZZLED (FZD) proteins. A WNT-FZD interaction may trigger several distinct intracellular signaling cascades, depending on the cellular context and the WNT-FZD couples involved. In humans, a deregulation of WNT signaling during embryonic development or adult life leads to congenital diseases and cancers, respectively. Understanding the great diversity of wnt genes and their biological functions is thus a modern-day challenge, which needs to be addressed, not only to foster general knowledge, but also to allow the identification of novel therapeutic targets and approaches towards future new medical applications. In the course of my Ph.D., I first aimed at describing the spatial and temporal expression patterns of all wnt and fzd genes present in the sea urchin, Paracentrotus lividus. Like humans, sea urchins belong to the deuterostome phyla. In addition, the early development of the sea urchin is relatively simple and is easy to interfere with, thanks to the experimental approaches available for this model. Moreover, the sea urchin lineage did not undergo whole genome duplications, unlike humans, exhibiting the same diversity of gene families, but with less redundancy within the subfamilies, thereby facilitating functional analyses. Thus, studying the mechanisms that drive sea urchin embryogenesis represent a valuable asset to provide insights into the conserved mechanisms controlling the development of deuterostomes. My results show that wnt and fzd genes are expressed in a dynamic fashion throughout P. lividus embryogenesis. Interestingly, until the gastrulation, the genes encoding FZD receptors are expressed in distinct territories that, taken together, cover almost the entire embryo. Accordingly, this work allowed me to establish a catalog of possible WNT-FZD couples likely to form during the embryogenesis of a deuterostome animal, based on the compatibility of their respective spatiotemporal distribution, and to further provide insights into the potential biological functions of these WNT and FZD proteins during this process. The second goal of my Ph.D. was to reconstruct the evolution of the WNT proteins and to determine whether an ancestral intrinsic function of WNTs is conserved within metazoans. To this end, I analyzed the composition of the wnt repertoires of seventeen metazoan species, the primary sequences of the WNT proteins they encode, the relative positions of the wnts within their respective genomes, and, for selected species, the genomic environment of their wnts. In addition, I investigated whether three sponge WNT ligands and an ancestral WNT sequence, which was calculated from a sample of metazoan WNT sequences, are able to trigger Wnt signaling pathways, when expressed in three planulozoan (cnidarian and bilaterian) species. The data obtained during this study allows me to propose a model for the diversification of wnt genes in metazoans and revealed conserved intrinsic functional capabilities for the WNT ligands. To conclude, my work provides insights into the evolution and functional properties of the main activators of the metazoan Wnt signaling pathways, the WNT proteins. A model is given on how an ancestral wnt gene diversified to give birth to the modern-day wnt repertoires, of which components were found to possess the conserved ability to bind to FRIZZLED receptors and trigger downstream cascades. Moreover, this study includes a detailed description of the spatial and temporal expression of WNT ligands and their FZD receptors, during the embryogenesis of a deuterostome animal, the sea urchin Paracentrotus lividus, allowing the identification of WNT/FZD couples that are likely to interact. The biological functions of these WNT-FZD couples, and their evolution within metazoans remain however to be explored.
Keywords : Wnt ligands Evolution
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Submitted on : Friday, September 24, 2021 - 2:00:59 PM
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  • HAL Id : tel-03353876, version 1


Nicolas Robert. Evolution de la famille de gènes wnt, l’un des principaux activateurs des voies de signalisation Wnt, au cours du développement des métazoaires. Biologie du développement. Université Pierre & Marie Curie - Paris 6, 2006. Français. ⟨tel-03353876⟩



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