Wnt and Src signals converge on YAP‐TEAD to drive intestinal regeneration

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.

DNA-damage induced cell death in yap1;wwtr1 mutant epidermal basal cells

“…This increase may create an increasingly rigid environment (Engler et al, 2006) that perhaps results in greater baseline genomic stress in the developing EBCs, and thus require survival signals to counteract this stress. Previous investigations have already shown how Yap1 plays instrumental roles in providing this survival signal, including driving the expression of Survivin, under genomic stress (Guillermin et al, 2021;Ma et al, 2016). However, our Western Blot assay did not find downregulation of Survivin in zebrafish yap1;wwtr1 double mutants (data not shown), presumably as Survivin is also a key player in cellular proliferation (Nair et al, 2013), which is not impeded in mutants.…”

“…When cells are challenged with DNA damaging agents including doxorubicin (Ma et al, 2016) and radiation (Guillermin et al, 2021), YAP1, as a co-transcription factor of Teads, is localised in the nucleus to drive expression of pro-survival genes. Indeed, transgenic expression of Yap1 in murine livers upregulates the expression of Survivin (Birc5) in hepatocytes, protecting these cells from apoptosis when treated with a pro-apoptotic agent, Jo-2 (Dong et al, 2007).…”

“…Indeed, transgenic expression of Yap1 in murine livers upregulates the expression of Survivin (Birc5) in hepatocytes, protecting these cells from apoptosis when treated with a pro-apoptotic agent, Jo-2 (Dong et al, 2007). On the other hand, genetic knock-down of Yap1 or inhibition of YAP1 nuclear localisation exaggerates apoptosis in cells exposed to chemo-and radiotherapy (Guillermin et al, 2021;Ma et al, 2016). Thus, YAP1 executes its pro-survival function in the nucleus by driving the expression of target genes.…”

Integrated Analysis of mRNA-Seq and MiRNA-Seq Reveals the Molecular Mechanism of the Intestinal Immune Response in Marsupenaeus japonicus Under Decapod Iridescent Virus 1 Infection

“…The Hippo signaling pathway, originally considered to be a growth regulation pathway, has recently been found to play indispensable roles in the regulation of innate anti-bacterial immunity and anti-viral immunity ( 85 , 86 ). Several studies have demonstrated that both the Wnt signaling pathway and Hippo signaling pathway are involved in intestinal regeneration and intestinal homeostasis ( 87 – 90 ). These results imply that shrimp intestinal miRNAs participate in the intestinal immune response against DIV1 infection by regulating genes in the immune signaling pathway.…”

Cell Models for Chromosome 20q11.21 Amplification and Drug Sensitivities in Colorectal Cancer

“…Yes-associated protein 1 (YAP1), a transcription factor of the Hippo pathway, comes up in the dependency screening of 20q amplified colorectal cancer cell lines, confirming a key role of the pathway in colorectal cancer. YAP1 co-operates with transcription factors TAZ and TEAD in transcription of genes involved in proliferation following tissue damage and promoting regeneration in the gut [ 27 ]. In colorectal cancer, aberrant signals from cancer-associated pathways, such as WNT and activated KRAS, activate Hippo to promote tumor growth and metastasis [ 28 ].…”