Cardiac Damage and Its Repair

InDrosophila, the Hippo-signaling pathway is awell-known orchestrator of organismal size. Probing whether these mechanisms also mould organogenesis in mammals, James Martin and colleagues disrupted multiple Hippo pathway components in the developing mouse heart. These targets for conditional knockout include the MST kinases (the mammalian Hippo homologues), Salvador (a scaffold protein that binds to MST kinases), and the kinase LATS2 (a substrate of MST1/2). They show that disruption of this pathway stimulates overgrowth of the heart due to an increase in cardiomyocyte proliferation, which leads to additional malformations, including defects in the ventricular septum. Further analysis showed that Wnt target genes are upregulated upon loss of the Hippo pathway and that reducing levels of b-catenin (a core mediator of Wnt signaling) suppressed cardiac overgrowth. Moreover, the authors report a new element in the crosstalk between the Hippo and Wnt pathways. When Hippo is inactive, the LATS2 substrate YAP is not phosphorylated and accumulates in the nucleus, where it directly interacts with b-catenin. The resulting complex is recruited to growth-promoting genes, including Sox2 and Snai2, activating their transcription. Future work may determine whether diminished signaling via this pathway might contribute to the pathological reactivation of developmental programs in cardiac hypertrophy. Heallen, T., et al. (2011). Science 332, 458–461.