Transcription factors SOX4 and SOX9 cooperatively control development of intrahepatic bile ducts

In developing liver, cholangiocytes derive from the hepatoblasts and organize to form the bile ducts. Earlier work has shown that SOX9 is transiently required for bile duct development, raising the question of the potential involvement of other SOX factors in biliary morphogenesis. Here we identify SOX4 as a new regulator of biliary development. Inactivation of SOX4, 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 TGFβ, 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 laminin α5, which promotes 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.