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.
Highlights
How organ size is regulated in mammals during development and how tissue homeostasis is maintained in adults is a fundamental question that is relevant for normal organ function as well as in pathological situations such as cancer
Several theories have been put forth that address how organs achieve their normal size during embryogenesis, how they regulate their size proportionally with overall body size during neonatal and prepubescent growth, and how cell death and cell proliferation is balanced in adults to maintain tissue homeostasis and normal organ size.[1]
Different theories differ among mechanisms that underlie organ size control and homeostasis, they all converge on fundamental cellular processes such as cell division and survival
Summary
How organ size is regulated in mammals during development and how tissue homeostasis is maintained in adults is a fundamental question that is relevant for normal organ function as well as in pathological situations such as cancer. Several theories have been put forth that address how organs achieve their normal size during embryogenesis, how they regulate their size proportionally with overall body size during neonatal and prepubescent growth, and how cell death and cell proliferation is balanced in adults to maintain tissue homeostasis and normal organ size.[1] different theories differ among mechanisms that underlie organ size control and homeostasis, they all converge on fundamental cellular processes such as cell division and survival.
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