Pygopus Is Required for Age-dependent Maintenance of Heart Function Independent of Canonical Wnt Signaling. Karen Ocorr¹, Min Tang², Wuzhou Yuan², Xiushan Wu², Rolf Bodmer¹. 1) Dept Neuroscience & Aging, Sanford-Burnham Medical Research Institute, La Jolla, CA; 2) The Center for Heart Development, College of Life Science, Hunan Normal University, Changsha Hunan Province, P.R. 410081.

   Age-dependent decline in cardiac function has been demonstrated for both flies and humans. Although important for cardiac development and differentiation, the role of Wnt signaling components in the adult myocardium or with age is unclear. Of these components, pygopus (pygo) was originally identified as a nuclear adapter, along with -catenin, that promotes TCF-dependent Wnt target gene transcription, but its role in maintaining adult cardiac performance is unknown. In this study, we show that Pygo is prominently expressed in the adult myocardial cells, and that pygo function is strongly required for cardiac performance and myocardial integrity, unlike other canonical Wnt pathway components tested. Cardiac-specific knockdown of pygo in the adult heart results in increased arrhythmias, reduced contractility (systolic dysfunction) and myofibrillar disorganization. In contrast, cardiac-specific disruption of Wnt signaling components -catenin/armadillo and TCF/pangolin results in relatively weak heart defects compared to pygo loss-of-function. pygo also failed to exhibit a significant genetic interaction with these canonical Wnt components, as well as with TCF target Ubx and with mediator complex genes associated with canonical Wnt signaling, suggesting that pygo function in the adult heart does not require canonical Wnt signaling. Taken together, our studies suggest a novel role for pygo that is critical for adult heart function and structural integrity, but unexpectedly this role is likely independent of canonical Wnt signaling.