The Hippo signaling pathway – a genetic program thought to play a central role in organ development – does not instruct normal organ growth in flies and mice, according to a new study.
The findings, which challenge a long-standing idea about the role of Hippo signaling, suggest the need to re-evaluate the pathway's function in other biological contexts, including cancer and organ regeneration. The Hippo signaling pathway is widely considered to be a master regulator of normal organ growth. Studies in flies and mice have shown that mutations in parts of the Hippo pathway can result in organ overgrowth.
Based on these observations, researchers suggest that loss-of-function mutations in the core kinases or over-expression of the transcriptional coactivators Yap/Taz/Yki up-regulates the expression of genes that induce cell proliferation, cell survival, and tissue growth. It's thought that Yap/Taz/Yki are active and drive cell proliferation during the growth phase of an organ but are inactivated when the organ is fully grown. However, not all findings fit this standard model.
Weronika Kowalczyk and colleagues re-evaluated the function of Hippo signaling during organ growth in Drosophila imaginal disc cell-derived structures like wings and eyes, as well as the mouse liver. Contrary to the current model, Kowalczyk et al. found that removing Hippo signaling did not impair the ability of the studied organs to grow to their normal size. What's more, the authors found that the transcriptional activity of Yap/Taz/Yki did not correlate with cell proliferation or normal organ development. Although Kowalczyk et al. discovered that the Hippo pathway does not instruct normal organ growth, the authors did identify several Hippo pathway genes that were required for overgrowth, suggesting that Hippo signaling plays a role in activating abnormal genetic programs that lead to ectopic organ development.
Kowalczyk, W., et al. (2022) Hippo signaling instructs ectopic but not normal organ growth. Science. doi.org/10.1126/science.abg3679.