Dual role of YAP and TAZ in renewal of the intestinal epithelium

Abstract

The rapidly self-renewing intestinal epithelium represents an exquisite model for stem cell biology. So far, genetic studies in mice have uncovered crucial roles for several signalling pathways in the tissue. Here we show, by using intestine-specific gene transfer (iGT), that Hippo signalling effectors, YAP and TAZ, promote both the proliferation of intestinal stem/progenitor cells and their differentiation into goblet cells. These functions of YAP/TAZ are regulated by the upstream Hippo pathway kinases MST1/2 and LATS1/2. Moreover, we identify TEADs and Klf4 as partner transcription factors of YAP/TAZ in the proliferation and differentiation processes, respectively. These results indicate that Hippo signalling plays a dual role in renewal of the intestinal epithelium through the regulation of two different processes, stem/progenitor cell proliferation and differentiation into goblet cells, using two different types of transcription factor. Moreover, iGT should provide a robust platform to elucidate molecular mechanisms of intestinal epithelium self-renewal.

Regulation and plasticity of intestinal stem cells during homeostasis and regeneration

“…Genetic inhibition of the Hippo pathway increases ISC proliferation in Drosophila (Karpowicz et al, 2010). Imajo and colleagues report similar proliferative effects after YAP activation in the murine intestine (Imajo et al, 2014). However, overexpression of YAP-S127A, a phospho-deficient mutant that readily translocates to the nucleus, decreased proliferation and inhibited Wnt signaling in vivo (Barry et al, 2013).…”

“…These paradoxical observations can be reconciled by postulating separate cytoplasmic and nuclear functions of YAP/TAZ. YAP/ TAZ have been shown to directly bind to Axin and inhibit Wnt signaling in an overexpression system (Azzolin et al, 2014;Imajo et al, 2014). In this scenario, YAP/TAZ would thus act as part of the β-catenin destruction complex in HEK cells, and mediate the recruitment of the β-catenin E3 ligase β-TrCP, targeting it for destruction (Azzolin et al, 2014).…”

Role of Src Family Kinases in Regulation of Intestinal Epithelial Homeostasis

“…YAP is thought to promote cell proliferation and differentiation by regulating the expression of its target genes in various cell types, including IECs (37,38). Indeed, YAP was previously shown to be predominantly expressed in crypts of the small intestine (45).…”

“…YAP and TAZ function as transcriptional coactivators in the Hippo signaling pathway, with YAP being thought to promote cell proliferation and differentiation by regulating the expression of its target genes in various cell types, including IECs (37,38). Activation of the Hippo signaling pathway upstream of YAP results in the degradation of YAP in the cytoplasm in a manner dependent on the ubiquitin-proteasome system.…”

Lineage specification in the mouse preimplantation embryo

“…This suggests that YAP can have different DNA-binding partners to activate target genes (Imajo et al, 2015) or that parallel signalling cascades could compensate for the loss of TEAD4 in low O 2 conditions. The analysis of TE-specific enhancers of Cdx2 reveals that Notch signalling cooperates with Hippo/YAP signalling (Rayon et al, 2014) for full activation of Cdx2 expression.…”