SOX9 is a key factor for the postnatal maturation of the intrahepatic bile duct network.

It is widely recognized that sex-determining region Y-box 9 (SOX9) plays a critical role in the development of intrahepatic bile ducts (IHBDs) during the embryonic stage. IHBDs are composed of two distinct networks: a hierarchical network and a homogeneous network. The hierarchical network consists of large bile ducts that run along the portal veins (PVs) and branch into smaller bile ducts, forming a reticular structure around the PVs. By contrast, the homogeneous network is an early tubular structure composed of bile ductules surrounding the PVs and serves as a precursor to the mature hierarchical network. This study examined the role of SOX9 in the postnatal development of these networks using three-dimensional imaging analysis and a mouse model in which SOX9 deficiency predominates after birth. Our findings indicate that SOX9 is essential for the maturation and structural organization of the IHBD, particularly in terms of facilitating the proper connection between bile ductules and bile canaliculi. Furthermore, transcriptional changes in Sox9 conditional knockout mice activated compensatory pathways involved in bile acid transport and metabolism, while downregulating intercellular adhesion pathways, thereby impairing cholangiocyte adhesion and structural integrity. These results indicate that SOX9 plays a more pivotal role in the development of the bile duct network than previously thought.