The Hippo signaling pathway restricts the oncogenic potential of an intestinal regeneration program

TLDR

Hippo signaling’s role in organ size is known, but its function during tissue regeneration remains largely unknown. The study uses a dextran sodium sulfate–induced colonic regeneration model to investigate this. Regenerating crypts show elevated YAP; loss of YAP does not affect normal homeostasis but severely impairs DSS‑induced regeneration, whereas YAP hyperactivation causes early polyp formation, indicating that YAP must be tightly regulated to permit compensatory proliferation while preventing oncogenic potential.

Abstract

Although a developmental role for Hippo signaling in organ size control is well appreciated, how this pathway functions in tissue regeneration is largely unknown. Here we address this issue using a dextran sodium sulfate (DSS)-induced colonic regeneration model. We find that regenerating crypts express elevated Yes-associated protein (YAP) levels. Inactivation of YAP causes no obvious intestinal defects under normal homeostasis, but severely impairs DSS-induced intestinal regeneration. Conversely, hyperactivation of YAP results in widespread early-onset polyp formation following DSS treatment. Thus, the YAP oncoprotein must be exquisitely controlled in tissue regeneration to allow compensatory proliferation and prevent the intrinsic oncogenic potential of a tissue regeneration program.