title: Transcription factors SOX4 and SOX9 cooperatively control development of bile ducts.
abstract: In developing liver, cholangiocytes derive from the hepatoblasts and organize to form the bile ducts. Earlier work has shown that the SRY-related High Mobility Group box transcription factor 9 (SOX9) is transiently required for bile duct development, raising the question of the potential involvement of other SOX family members in biliary morphogenesis. Here we identify SOX4 as a new regulator of cholangiocyte development. Liver-specific inactivation of SOX4, combined or not with inactivation of SOX9, affects cholangiocyte differentiation, apico-basal polarity and bile duct formation. Both factors cooperate to control the expression of mediators of the Transforming Growth Factor-β, Notch, and Hippo-Yap signaling pathways, which are required for normal development of the bile ducts. In addition, SOX4 and SOX9 control formation of primary cilia, which are known signaling regulators. The two factors also stimulate secretion of laminin α5, an extracellular matrix component promoting bile duct maturation. We conclude that SOX4 is a new regulator of liver development and that it exerts a pleiotropic control on bile duct development in cooperation with SOX9.
authors.affiliation: Université catholique de Louvain, de Duve Institute, Avenue Hippocrate 75/B1-7503, Brussels 1200, Belgium. Electronic address: alexis.poncy@uclouvain.be.
authors.forename: Alexis
authors.initials: A
authors.lastname: Poncy
authors.affiliation: Université catholique de Louvain, de Duve Institute, Avenue Hippocrate 75/B1-7503, Brussels 1200, Belgium. Electronic address: aline.antoniou@bordet.be.
authors.forename: Aline
authors.initials: A
authors.lastname: Antoniou
authors.affiliation: Université catholique de Louvain, de Duve Institute, Avenue Hippocrate 75/B1-7503, Brussels 1200, Belgium. Electronic address: sabine.cordi@uclouvain.be.
authors.forename: Sabine
authors.initials: S
authors.lastname: Cordi
authors.affiliation: Université catholique de Louvain, de Duve Institute, Avenue Hippocrate 75/B1-7503, Brussels 1200, Belgium. Electronic address: christophe.pierreux@uclouvain.be.
authors.forename: Christophe E
authors.initials: CE
authors.lastname: Pierreux
authors.affiliation: Université catholique de Louvain, de Duve Institute, Avenue Hippocrate 75/B1-7503, Brussels 1200, Belgium. Electronic address: patrick.jacquemin@uclouvain.be.
authors.forename: Patrick
authors.initials: P
authors.lastname: Jacquemin
authors.affiliation: Université catholique de Louvain, de Duve Institute, Avenue Hippocrate 75/B1-7503, Brussels 1200, Belgium. Electronic address: frederic.lemaigre@uclouvain.be.
authors.forename: Frédéric P
authors.initials: FP
authors.lastname: Lemaigre
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis; D000818:Animals; D001653:Bile Ducts, Intrahepatic / Q000196:embryology* / Q000254:growth & development; D018797:Cell Cycle Proteins; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D018507:Gene Expression Regulation, Developmental; D000090683:Hippo Signaling Pathway; D007797:Laminin / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D038081:Organogenesis / Q000235:genetics; D010750:Phosphoproteins / Q000096:biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis; D051880:Receptors, Notch / Q000096:biosynthesis; D055758:SOX9 Transcription Factor / Q000096:biosynthesis / Q000235:genetics*; D055751:SOXC Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D007797:Laminin; D010750:Phosphoproteins; D051880:Receptors, Notch; D055758:SOX9 Transcription Factor; D055751:SOXC Transcription Factors; C489990:Sox4 protein, mouse; C527933:Sox9 protein, mouse; D016212:Transforming Growth Factor beta; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse; C097043:laminin alpha5; D017346:Protein Serine-Threonine Kinases
keywords: Biliary tract; Liver development; SOX transcription factors; Transcriptional network