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  • br Discussion In this study we show that conditional loss

    2021-09-16


    Discussion In this study, we show that conditional loss of Yap/Taz in the endocardium results in a thin compact myocardium and early postnatal lethality. We also report that loss of Yap/Taz in the endocardium leads to diminished expression of Nrg1, which is a crucial endocardial-derived factor that shapes the myocardium (Brutsaert, 2003, Ford et al., 1999, Lai et al., 2010, Meyer and Birchmeier, 1995, Rentschler et al., 2002). The myocardial phenotype of hearts with Yap/Taz-deficient endocardium is partially rescued by addition of recombinant Nrg1. Moreover, we demonstrate that Yap can occupy the promoter/enhancer regions of Nrg1, suggesting that Yap may directly regulate Nrg1 expression. This study reveals a novel Yap/Taz-dependent regulation of Nrg1 in the endocardium that is required for proper myocardial development. Both the Hippo pathway and the ErbB pathway have been implicated in cell-autonomous control of cardiomyocyte proliferation during development and after injury, and both are attractive therapeutic targets to enhance cardiac regeneration. Our results highlight an unexpected convergence of these pathways in endocardial FG2216 australia where Yap/Taz function to regulate Nrg1 expression. Nrg1 secretion from endocardium activates ErbB2/4 receptors on adjacent cardiac myocytes, and it is attractive to hypothesize that active ErbB signaling in cardiac myocytes once again converges with Hippo signaling to regulate proliferation. Indeed, recent studies in mammary cells indicate that Nrg1 binding to ErbB receptors induces cleavage of ErbB4 and subsequent liberation of an intracellular domain (ICD) that binds Yap via the WW domain (Haskins et al., 2014). The Yap:ErbB4-ICD complex enters the nucleus, binds TEAD factors, and induces the expression of Yap-dependent proliferation-associated genes. Assuming a similar capacity for ErbB4/Yap interactions in cardiac myocytes, we speculate that Hippo activation in endocardium results, indirectly, in activation of Yap/Taz target FG2216 australia genes in cardiac myocytes in a Nrg1/ErbB-dependent manner. Thus, cell-autonomous and non-cell-autonomous Hippo signaling may be linked via Nrg1/ErbB signaling to regulate cardiogenesis. A growing body of evidence identifies endothelium as an important source of paracrine signaling during organogenesis. For example, endothelial cells promote liver organogenesis during development even before formation of the regional vasculature (Freedman et al., 2007, Matsumoto et al., 2001). In the heart, disruption of multiple pathways, including PlexinD1 (Gitler et al., 2004), Neurofibromin (Gitler et al., 2003), Notch (de la Pompa and Epstein, 2012, High and Epstein, 2008) and Shp2 (Araki et al., 2009, Lauriol et al., 2016), can result in structural or functional heart disease despite the presence of apparently intact blood vessels and oxygen-carrying capacity. In neural crest cells, we have previously shown that Notch and Hippo signaling can interact since Yap/Taz functionally bind to Rbp-J to regulate Notch target genes (Manderfield et al., 2015). Others have provided evidence that ErbB signaling is disrupted when the Notch pathway components Numb and Numb-like are deleted (Hirai et al., 2017). It will be of interest to determine how these and additional pathways intersect to form the network of endocardial signaling that impacts upon cardiac myocyte homeostasis. In the setting of a major ischemic episode, the mammalian heart fails to mount a robust regenerative response sufficient to replace the loss of cardiomyocytes. The Nrg1-ErbB signaling axis has been a focus of translational efforts to ameliorate ischemia-reperfusion injury and to enhance regeneration. Nrg1 stimulates proliferation of mono-nucleated mouse cardiomyocytes and enhances cardiac repair after injury in both mice and zebrafish (Bersell et al., 2009, Gemberling et al., 2015). Gain- and loss-of-function studies in mice involving both ErbB2 and ErbB4 support the rationale for further studies focused on the therapeutic potential of the Nrg1-ErbB signaling pathway (Bersell et al., 2009, D'Uva et al., 2015, D'Uva and Tzahor, 2015, Polizzotti et al., 2015). Indeed, clinical trials using recombinant Nrg1 have been initiated (Gao et al., 2010, Jabbour et al., 2011). Our results suggest that endothelial Yap/Taz activity may be a relevant therapeutic target for modulation of Nrg1-ErbB signaling. Further studies to determine if endothelial Hippo signaling could act as a sensor to regulate myocardial regeneration in neonatal or adult life will be of great interest.