Hippo pathway coactivators Yap and Taz are required to coordinate mammalian liver regeneration

Abstract

The mammalian liver has a remarkable capacity for repair following injury. Removal of up to two-third of liver mass results in a series of events that include extracellular matrix remodeling, coordinated hepatic cell cycle re-entry, restoration of liver mass and tissue remodeling to return the damaged liver to its normal state. Although there has been considerable advancement of our knowledge concerning the regenerative capacity of the mammalian liver, many outstanding questions remaining, such as: how does the regenerating liver stop proliferating when appropriate mass is restored and how do these mechanisms relate to normal regulation of organ size during development? Hippo pathway has been proposed to be central in mediating both events: organ size control during development and following regeneration. In this report, we examined the role of Yap and Taz, key components of the Hippo pathway in liver organ size regulation, both in the context of development and homeostasis. Our studies reveal that contrary to the current paradigms that Yap/Taz are not required for developmental regulation of liver size but are required for proper liver regeneration. In livers depleted of Yap and Taz, liver mass is elevated in neonates and adults. However, Yap/Taz-depleted livers exhibit profound defects in liver regeneration, including an inability to restore liver mass and to properly coordinate cell cycle entry. Taken together, our results highlight requirements for the Hippo pathway during liver regeneration and indicate that there are additional pathways that cooperate with Hippo signaling to control liver size during development and in the adult. Liver cancer treatment could benefit from new findings detailing how a signalling pathway helps the liver to regenerate. Mammalian livers have an impressive ability to regrow after injury, and the Hippo signalling pathway has been identified as a key mediator involved in both healing the liver and controlling its size. Randy Johnson at the MD Anderson Cancer Center in Houston, USA, and co-workers generated mice lacking two coactivator proteins from the Hippo pathway called Yap and Taz. They found that the mutant mice showed no difference in liver development, but were less able to completely recover their liver mass after two-thirds of it was removed. This suggests that Yap and Taz are required to mount efficient regenerative responses, for example to cancer. Therapies that target these proteins could potentially inhibit liver cancer tumour progression.