Implication du facteur de transcription HNF-6 dans l'hématopoïèse
(2002)
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- The identification of transcription factors that participate to the mechanisms of lymphoid development have helped to understand this process. One way to study the role of these factors is to analyze the phenotype of mice in which the gene coding for e particular transcription factor has been inactivated (knockout mice). <BR> Hepatocyte nuclear factor-6 (HFN-6); discovered in the laboratory, is the prototype of a new class, called Onecut, of evolutionarily conserved proteins that contain a single cut domain and a divergent homeodomain. HNF-6 is required for proper development of the biliary tract and of the pancreas, which illustrates the role of this factor in development. Preliminary datas suggested that HNF-6 could also control hematopoiesis. <BR> In the course of this doctoral work, we first showed that hfn6 is not expressed constitutively in hematopoietic tissues from adult or fetal mice, irrespective of the strain of mice and of their immunisation status. However, we demonstrated in vitro that cytokines like oncostatin M are able to induce hnf6 expression. <BR> We discovered that the inactivation of the hnf6 gene in the mouse leads to decreased B lumphopoiesis and to increased granulopoiesis. We focussed on B lymphopoiesis and showed that HNF-6 regulates in the fetal liver, but not in adult bone marrow. Our data suggested that HNF-6 controls an early stage o B cell development. They also showed that this control is indirect and involves an influence of nonhematopoietic cells of fetal liver on B cell precursors. Indeed, parenchymal cells, but not hematopoietic cells, expressed hnf6. Moreover, hematopoietic cells from hnf6-/- fetal liver could reconstitute the lymphoid system when injected into scid mice. Gene expression analysis in the liver of hnf6-/- embryos allowed us to exclude in these animals altered expression on extrinsic known to be implicated in B lymphopoiesis such as IL-7, IGF-I, IGF-II, SCF and OSMR. Modifications of gene expression in the HGF signaling pathway were identified, but our experiments excluded their involvement in the lymphoid phenotype of hnf6-/- mice. However, our observations indicated that this phenotype could result from excessive signaling through the TGFβ pathway. <BR> Thus, hnf6 knockout mice are the first example of a liver-specific defect of hematopoietis and provide an original model for studying the interaction between hematopoietic cells and cells of the hepatic microenvironment
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Bouzin, C. (2002). Implication du facteur de transcription HNF-6 dans l’hématopoïèse. https://hdl.handle.net/2078.5/110867