Cardiomyocyte proliferation is crucial for embryonic heart development, yet the signalling pathways that regulate proliferation are incompletely defined. Olson and colleagues now reveal a central role for the Hippo pathway protein Yap in this process (Sci. Signal. 4, ra70; 2011).

Targeted deletion of Yap in mouse cardiac progenitor cells decreased their proliferation and resulted in embryonic lethality. In contrast, overexpressing constitutively active Yap in the heart increased the number of cardiomyocytes. Further analysis of these transgenic hearts revealed upregulation of insulin-like growth factor 1 receptor (IGF-1R) and β-catenin levels, with associated induction of their downstream targets. This raises the possibility that Yap-mediated cardiomyocyte proliferation requires the IGF and β-catenin signalling pathways. Knockdown of IGF-1R and β-catenin abolished the Yap-dependent increase in cardiomyocyte cell division.

The authors went on to show that the transcriptional activity of Yap is required for upregulating β-catenin signalling. Intriguingly, Yap also induced phosphorylation and inhibition of GSK3β, which should further increase β-catenin accumulation. Constitutively active Yap stimulated the IGF signalling pathway in the absence of IGF, whereas inhibiting IGF signalling limited the Yap-dependent increase in β-catenin activity. Together, these results suggest that Yap regulates the IGF and β-catenin signalling pathways to promote embryonic heart growth.