Transcription factors SOX4 and SOX9 cooperatively control development of bile ducts

Dev Biol. 2015 Aug 15;404(2):136-48. doi: 10.1016/j.ydbio.2015.05.012. Epub 2015 May 29.


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.

Keywords: Biliary tract; Liver development; SOX transcription factors; Transcriptional network.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / biosynthesis
  • Animals
  • Bile Ducts, Intrahepatic / embryology*
  • Bile Ducts, Intrahepatic / growth & development
  • Cell Cycle Proteins
  • Cell Differentiation / genetics
  • Cells, Cultured
  • Gene Expression Regulation, Developmental
  • Hippo Signaling Pathway
  • Laminin / metabolism
  • Mice
  • Mice, Knockout
  • Organogenesis / genetics
  • Phosphoproteins / biosynthesis
  • Protein Serine-Threonine Kinases / biosynthesis
  • Receptors, Notch / biosynthesis
  • SOX9 Transcription Factor / biosynthesis
  • SOX9 Transcription Factor / genetics*
  • SOXC Transcription Factors / biosynthesis
  • SOXC Transcription Factors / genetics*
  • Transforming Growth Factor beta / biosynthesis
  • YAP-Signaling Proteins


  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • Laminin
  • Phosphoproteins
  • Receptors, Notch
  • SOX9 Transcription Factor
  • SOXC Transcription Factors
  • Sox4 protein, mouse
  • Sox9 protein, mouse
  • Transforming Growth Factor beta
  • YAP-Signaling Proteins
  • Yap1 protein, mouse
  • laminin alpha5
  • Protein Serine-Threonine Kinases