embj.2020105770.pdf (16.49 MB)
Wnt and Src signals converge on YAP-TEAD to drive intestinal regeneration.
journal contributionposted on 2021-07-21, 13:15 authored by Oriane Guillermin, Nikolaos Angelis, Clara M Sidor, Rachel Ridgway, Anna Baulies, Anna Kucharska, Pedro Antas, Melissa R Rose, Julia Cordero, Owen Sansom, Vivian SW Li, Barry J Thompson
Wnt signalling induces a gradient of stem/progenitor cell proliferation along the crypt-villus axis of the intestine, which becomes expanded during intestinal regeneration or tumour formation. The YAP transcriptional co-activator is known to be required for intestinal regeneration, but its mode of regulation remains controversial. Here we show that the YAP-TEAD transcription factor is a key downstream effector of Wnt signalling in the intestine. Loss of YAP activity by Yap/Taz conditional knockout results in sensitivity of crypt stem cells to apoptosis and reduced cell proliferation during regeneration. Gain of YAP activity by Lats1/2 conditional knockout is sufficient to drive a crypt hyperproliferation response. In particular, Wnt signalling acts transcriptionally to induce YAP and TEAD1/2/4 expression. YAP normally localises to the nucleus only in crypt base stem cells, but becomes nuclear in most intestinal epithelial cells during intestinal regeneration after irradiation, or during organoid growth, in a Src family kinase-dependent manner. YAP-driven crypt expansion during regeneration involves an elongation and flattening of the Wnt signalling gradient. Thus, Wnt and Src-YAP signals cooperate to drive intestinal regeneration.
Crick (Grant ID: 10105, Grant title: Li FC001105) Crick (Grant ID: 10180, Grant title: Thompson FC001180)