title: Gene regulation by homeobox transcription factor Prox1 in murine hepatoblasts.
abstract: The homeobox transcription factor Prox1 is expressed in embryonic hepatoblasts and remains expressed in adult hepatocytes. Prox1-null mice show severe deficiencies in liver development, although the underlying mechanisms are unknown. We have studied the effects of Prox1 on the transcriptional profile of met-murine hepatocytes (MMH) obtained on embryonic day 14 (ED14). These immortalized murine hepatoblasts express numerous hepatoblast markers, but not Prox1. We have performed stable transfection with Prox1 cDNA, analyzed the transcriptome with Agilent mouse whole-genome microarrays, and validated genes by quantitative reverse transcription/polymerase chain reaction. We have observed the up-regulation of 22 genes and the down-regulation of 232 genes, by more than 12-fold. Many of these genes are involved in metabolic hepatocyte functions and may be regulated by Prox1 directly or indirectly, e.g., by the down-regulation of hepatocyte nuclear factor 4alpha. Prox1 induces the down-regulation of transcription factors that are highly expressed in neighboring endodermal organs, suggesting a function during hepatoblast commitment. Prox1 does not influence the proliferative activity of MMH but regulates genes involved in liver morphogenesis. We have observed the up-regulation of both type-IValpha3 procollagen and functionally active matrix metalloproteinase-2 (MMP-2), an observation that places Prox1 at the center of liver matrix turnover. This is consistent with MMP-2 expression in hepatoblasts during liver development and with the persistence of a basal lamina around the liver bud in Prox1-deficient mice. Our studies suggest that Prox1 is a multifunctional regulator of liver morphogenesis and of hepatocyte function and commitment.
authors.affiliation: Children's Hospital, Pediatrics I, Georg August University, Robert-Koch-Strasse 40, 37075, Göttingen, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Papoutsi
authors.forename: Jozsef
authors.initials: J
authors.lastname: Dudas
authors.forename: Jürgen
authors.initials: J
authors.lastname: Becker
authors.forename: Marco
authors.initials: M
authors.lastname: Tripodi
authors.forename: Lennart
authors.initials: L
authors.lastname: Opitz
authors.forename: Giuliano
authors.initials: G
authors.lastname: Ramadori
authors.forename: Jörg
authors.initials: J
authors.lastname: Wilting
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D019070:Cell Lineage / Q000235:genetics; D002478:Cells, Cultured; D024141:Collagen Type IV / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D022781:Hepatocytes / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000166:cytology / Q000196:embryology* / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D051379:Mice; D051381:Rats; D013234:Stem Cells / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D000098551:Prospero-Related Homeobox 1 Protein