Editors' ChoiceRegeneration

Hippo Checks Regeneration

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Science Signaling  09 Nov 2010:
Vol. 3, Issue 147, pp. ec342
DOI: 10.1126/scisignal.3147ec342

Many factors that stimulate cell proliferation in regenerating tissues are known, but few mechanisms for restricting proliferation during regeneration have been identified. Cai et al. used a mouse model of intestinal regeneration after damage by dextran sodium sulfate (DSS) to investigate whether signaling through the Hippo pathway, which limits organ size in diverse species, also plays a role in limiting regenerative proliferation. Knocking out Yap in the intestinal epithelium during embryonic development had no effect on intestinal morphology or function but impeded regeneration after DSS treatment, with DSS-treated Yap mutant epithelia showing less proliferation and more apoptosis in the colon compared to wild type (WT). Removal of the Hippo signaling component Sav1 caused increased intestinal epithelial cell proliferation, which was rescued by concomitant knockout of Yap, and male mice lacking Sav1 in the intestinal epithelia developed colonic polyps by 13 months of age, suggesting that Hippo signaling plays a role in limiting epithelial proliferation during normal homeostasis. Transient DSS treatment resulted in the development of colonic polyps by 3 months of age in mice lacking Sav1 in the intestinal epithelium but did not induce polyps in WT mice or those lacking only Yap or lacking both Yap and Sav1, indicating a critical requirement for Hippo signaling in limiting regenerative proliferation. These polyps were morphologically similar to sessile serrated polyps (SSPs) and did not show increased nuclear accumulation of β-catenin, but they did show increased nuclear accumulation of Yap, and some of them subsequently underwent adenomatous transformation and invaded the intestinal smooth muscle. SSPs removed from human patients showed increased nuclear accumulation of Yap compared with adjacent normal tissue but no nuclear accumulation of β-catenin. These findings support the notion that SSPs represent an alternative to β-catenin–dependent colorectal tumorigenesis and implicate the repression of Yap activity by Hippo signaling in this oncogenic pathway. The authors propose a model in which Hippo signaling activity in the intestinal epithelium keeps Yap inactive until regeneration is initiated and limits Yap activity to terminate proliferation when regeneration is complete.

J. Cai, N. Zhang, Y. Zheng, R. F. de Wilde, A. Maitra, D. Pan, The Hippo signaling pathway restricts the oncogenic potential of an intestinal regeneration program. Genes Dev. 24, 2383–2388 (2010). [Abstract] [Full Text]

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