Yap and Taz may regulate

Yap and Taz may regulate epicardial cell proliferation, EMT, and fate determination via multiple mechanisms. In this study, we provide evidence that Yap/Taz function in part by directly modulating Tbx18 and Wt1 expression. Members of the T-box family of transcription factors regulate a variety of developmental processes, including coronary vasculature development. Tbx18-deficient hearts show abnormal coronary vascular plexus formation due to impaired epicardial signaling, cell proliferation, and cell fate determination (Greulich et al., 2012, Wu et al., 2013). Tbx5, a gene mutated in Holt-Oram syndrome, is expressed in the PEO and epicardium. Tbx5 mutant hearts show abnormal coronary vasculature due to impaired production of epicardial-derived SB-334867 hydrochloride and their migration into the underlying myocardium (Diman et al., 2014, Hatcher et al., 2004). Interestingly, Yap and Taz interact with Tbx5 and regulate Tbx5-dependent gene programs (Murakami et al., 2005). Wt1 regulates epicardial EMT and myocardial growth by controlling Snail and E-cadherin expression (Martínez-Estrada et al., 2010), promoting Wnt/β-catenin signaling and expression of Wnt5a and Raldh2 (Guadix et al., 2011, von Gise et al., 2011). Yap can also regulate endocardial cell proliferation and EMT through modulation of TGF-β/Smad signaling (Zhang et al., 2014). Wt1 is expressed by tumor vessels, regulates PECAM1 expression and conditional deletion of Wt1 in endothelial cells results regression of tumor vascularization (Wagner et al., 2014). Recent studies have implicated Wt1 in cell fate determination in other tissues (Wen et al., 2014, Zhang et al., 2015). Since Yap and Wt1 are co-expressed in many tissues during development and disease, our findings may have broad relevance (Hiemer et al., 2014, Loeb et al., 2001).
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