Distribution and developmental timing of zebrafish liver innervation.

Hepatic innervation regulates multiple aspects of liver function, repair and regeneration, and liver denervation is associated with higher rates of metabolic disorders in humans. However, the mechanisms regulating the development of the hepatic nervous system, as well as the role of the hepatic nervous system in liver development and maturation, are still largely unknown. Zebrafish are a widely used model of liver development and regeneration, but hepatic innervation in zebrafish has not yet been described in detail. Here, we examine the extent and developmental timing of hepatic innervation in zebrafish. We demonstrate that innervation is restricted to large bile ducts and blood vessels in both juvenile and adult zebrafish livers, as we find no evidence for direct innervation of hepatocytes. Innervation contacting the periphery of the liver is visible as early as 72 h post-fertilization, while intrahepatic innervation is not established until 21 days post-fertilization. Therefore, zebrafish hepatic innervation resembles that of previously examined fish species, making them an excellent model to investigate both the role of the hepatic nervous system during liver maturation and the mechanisms governing the elaboration of the intrahepatic nerve network between fish and mammals.