Research ArticleDevelopment

Regulation of Insulin-Like Growth Factor Signaling by Yap Governs Cardiomyocyte Proliferation and Embryonic Heart Size

Sci. Signal.  25 Oct 2011:
Vol. 4, Issue 196, pp. ra70
DOI: 10.1126/scisignal.2002278

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Growing a Heart

Understanding the signaling pathways that regulate heart growth during development provides possible avenues for regenerative therapies. In the fruit fly, the Hippo signaling pathway acts to limit organ size during development, and recent evidence indicates that this pathway also restricts cardiac growth in embryonic mice. Among other targets, activation of Hippo inhibits the transcriptional coactivator Yap. Mice generated by Xin et al. with a cardiomyocyte-specific deficiency of Yap developed smaller hearts and died in utero. In contrast, mice expressing a constitutively active form of Yap in the heart had larger hearts because of increased cell proliferation. In cardiomyocytes, expression of the constitutively active form of Yap increased the activity of the insulin-like growth factor (IGF) pathway, which resulted in stabilization of β-catenin, a transcriptional effector of the Wnt signaling pathway that promotes cardiomyocyte proliferation. Thus, alleviating the Hippo pathway–mediated inhibition of Yap increases the activity of signaling pathways that increase the growth of the heart during development.

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