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Study of the role of the gene ovo/svb in the maintenance and the differentiation of intestinal stem cells in Drosophila

Abstract : The adult gut is a highly dynamic organ in charge of vital functions. Although cells that make up the gut are daily lost, intestinal homeostasis is maintained throughout adulthood due to self-renewal and differentiation properties of intestinal stem cells (ISCs). Here we show that the OvoL/Shavenbaby (Svb) transcription factor is required for adult gut homeostasis in flies. Recent work has shown that Svb is translated as a large sized repressor (Svb-REP), and then post-translationally processed in a shorter activator (Svb-ACT) in response to small peptides called Polished rice (Pri). We find that Svb is specifically expressed and processed into the activator isoform in adult gut progenitors, i.e. intestinal stem cells and enteroblats (ISC/EB). Svb-ACT is required to protect stem cells from apoptosis, and sufficient to promote their proliferation. Indeed, genetic assays reveal that Svb expression in ISCs is activated by two main mitogenic pathways, EGFR and Wnt. We identified an enhancer driving svb expression in gut progenitors and demonstrate that its activity relies on the direct binding of nuclear effectors of the EGFR and Wnt pathways. In addition, we delineated a second svb enhancer driving expression in differentiated enterocytes (ECs). Strikingly, we find that this is the Svb-REP isoform that is expressed and required within ECs. Svb-REP induces the differentiation of EB to EC and is required to maintain proper differentiation and survival of ECs. Finally, we show that Svb-ACT is required for the growth of ISC-derived tumors and that Svb-REP is sufficient to override deregulated signaling pathways, blocking tumorous behavior and leading to enterocyte differentiation. Taken together, our data in flies therefore demonstrate that controlled expression and maturation of the OvoL/Svb transcription factor plays a key role in the balance between stem cell maintenance/proliferation and enterocyte differentiation in the adult gut.
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Sandy Al Hayek. Study of the role of the gene ovo/svb in the maintenance and the differentiation of intestinal stem cells in Drosophila. Animal genetics. Université Paul Sabatier - Toulouse III; École Doctorale des Sciences et de Technologie (Beyrouth), 2019. English. ⟨NNT : 2019TOU30216⟩. ⟨tel-02934388⟩

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