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Caractérisation du récepteur nucléaire FXRα dans les cancers germinaux du testicule et étude fonctionnelle d’un nouveau variant

Abstract : The FXRα receptor, described in 4 forms in humans, acts as an inducible transcription factor capable of binding to DNA as a heterodimer with the RXRα (Retinoid X Receptor α) to regulate the expression of target genes. By controlling gene transcription, the FXRα receptor is involved not only in the regulation of lipid and carbohydrate metabolism, but also in the synthesis, transport as well as detoxification of bile acids and their metabolites. This is an essential function since the loss of activity and/or expression of this receptor, as well as inappropriate increase in bile acid concentrations, are associated with proliferation and apoptosis disorders described to promote neoplastic transformation especially in the liver and colon. Recently, the work of our team and others has shown that the FXRα receptor is expressed in the human testis from the first trimester of pregnancy as well as in the mouse fetal testis, and that its activity controls the balance of germline stem cells in this tissue. The strong reduction of FXRα abundance in testicular germ cell tumors (TGCT) samples highlighted by the team as well as the identification of a new FXRα isoform present in the liver and other tissues such as the testis, raise questions about the participation of this factor in the molecular etiology of the disease.These elements are the basis of the scientific project which aims to: i) study the function of a new FXRα variant produced by the alternative splicing of a part of its DNA binding domain, and ii) determine if the alterations in expression and/or function of FXRα proteins affect the biology of germline stem cells (GSC) and participate to the molecular etiology of TGT.The results of the thesis work show that the FXRα1 variant spliced for its exon 5 (ΔEx5) is expressed in several human tissues and cell lines as well as in mice in similar a pattern than those described of FXR proteins. By the absence of part of its DNA-binding domain, this variant is no longer able to bind to its target sequence at the DNA level or to activate FXRα-dependent transcriptional networks. Furthermore, this FXRα variant appears to exert a slightly dominant negative effect on the transcriptional activity of FXRα1 while exhibiting different interaction capabilities for its partner RXRα to lead to the loss of permissiveness of this dimer to transduce a signal via a yet unknown structural mechanism. Collectively, the results presented in this thesis have highlighted a novel FXRα variant that has yet to be informed for its ability to fine-tune the adaptive and/or metabolic response induced by bile acids. However, these data will contribute to further improve our knowledge of how splice variants can fit FXRα functions in tissues and then shed light on the contribution of this receptor in the control of GSC biology with an impact on fertility disorders and TGT development.
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Submitted on : Saturday, July 2, 2022 - 1:05:54 AM
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Manon Garcia. Caractérisation du récepteur nucléaire FXRα dans les cancers germinaux du testicule et étude fonctionnelle d’un nouveau variant. Physiologie [q-bio.TO]. Université Clermont Auvergne, 2021. Français. ⟨NNT : 2021UCFAC039⟩. ⟨tel-03712016⟩

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