Tbx5 as a cardiac regulator of Yap activity Heart failure is a leading cause of death worldwide. Unlike amphibians and fish the adult mammalian heart fails to regenerate after injury leading to a reduction in cardiomyocyte number, scar formation and reduced contractility. Recently, Hippo signaling has been shown to be an inhibitor of cardiomyocyte proliferation and cardiac regeneration after injury. In addition, Hippo signaling has also been shown to play an important role in cardiac development and in limiting heart size. These roles of Hippo signaling have been shown to be through regulation of Yap localization and Yap levels within cardiomyocytes. Inhibition of Hippo signaling or increased levels of nuclear Yap can promote regeneration in response to injury as well as lead to an increase in cardiac size during development. This presents Hippo signaling as a potential therapeutic target for cardiac repair. However, the Hippo pathway is also important in tumor suppression. Reductions of Hippo signaling and hyper activation of Yap have oncogenic functions, promoting cell proliferation and preventing cell death. Therefore, it is important to identify cardiac specifc regulators of Yap activity in order to induce cardiac regenerative without promoting wide spread oncogenic functions. Tbx5 a well-established cardiac transcription factor has been shown to interact with yap although an interaction in cardiomyocytes has not been explored. Based on preliminary data I hypothesize Tbx5 forms a complex with Yap in cardiomyocytes to regulate gene expression during heart development and regeneration. To test this I will employ both zebrafish and mouse models to compare the regenerative and non-regenerative heart. I will confirm a physical interaction between Tbx5 and Yap in cardiomyocytes as well as evaluate a functional interaction in cardiomyocyte production by performing knockdown and overexpression experiments. Additionally, I will identify downstream targets of this interaction that play a role in regeneration and development. This will further our understanding of factors involved in cardiac regeneration and may provide targets for development of therapeutics that repress Hippo signaling in a tissue specific manner.
Heart failure is a leading cause of death worldwide. Unlike amphibians and fish the adult mammalian heart fails to regenerate after injury leading to a reduction in cardiomyocyte number, scar formation and reduced contractility. A comparative analysis between zebrafish and mammalian hearts and identification of factors important for regeneration may be of use in regenerative medicine and in improving outcomes following myocardial infarction.
