Wnt and Src signals converge on YAP‐TEAD to drive intestinal regeneration. (5th May 2021)

• Record Type: Journal Article
• Authors: Guillermin, Oriane; Angelis, Nikolaos; Sidor, Clara M; Ridgway, Rachel; Baulies, Anna; Kucharska, Anna; Antas, Pedro; Rose, Melissa R; Cordero, Julia; Sansom, Owen; Li, Vivian S W; Thompson, Barry J
• Is Part Of: EMBO journal. Volume 40:Number 13(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-05-05
• Subjects: intestine -- regeneration -- Src -- Wnt -- YAP; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.2020105770
• Languages: English
• ISSNs: 0261-4189

Abstract

Abstract: 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. Synopsis: How the YAP‐TEAD transcriptional factor is regulated during intestinal repair and colorectal cancer remains debated. Here, genetic work identifies YAP and TEAD as transcriptional targets of Wnt signalling, with YAP nuclear localisation governed by Src family kinases, highlighting unexpected signal cooperation during murine tissue regeneration. Depletion of Yap/Taz increases crypt stem cell apoptosis and reduces proliferation during regeneration in vivo . Conditional activation of Yap/Taz by Lats1/2 depletion induces YAP nuclear localisation and crypt hyperplasia. Genetic activation of Wnt signalling induces transcript expression of YAP and TEAD1 / 2 / 4 in intestinal organoids or tumours. Irradiation‐induced nuclear localisation of YAP‐TEAD is regulated by Src family kinase, YAP‐TEAD activity and crypt regeneration are Wnt‐dependent. Abstract : Wnt transcriptionally controls YAP and TEAD expression to enable Src‐dependent activation of YAP‐TEAD activity during intestinal regeneration.