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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.

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Figure 1: Establishment of iGT.
Figure 2: Phenotypic analyses of the tissues transfected by iGT.
Figure 3: YAP/TAZ promote proliferation of stem/progenitor cells.
Figure 4: YAP/TAZ promote differentiation into goblet cells.
Figure 5: Hippo pathway components, LATS1/2, regulate intestinal epithelium renewal.
Figure 6: Hippo pathway components, MST1/2 and TEADs, regulate intestinal epithelium renewal.
Figure 7: Klf4 is a partner transcription factor of YAP/TAZ.
Figure 8: Cooperation of YAP/TAZ and Klf4 in promoting differentiation into goblet cells.

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Acknowledgements

We thank members of our laboratory for thoughtful discussion and helpful comments on the manuscript. This work was supported by grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan and Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology (to E.N. and M.I.).

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Contributions

M.I. and E.N. conceived and directed the project, and prepared the manuscript. M.I. carried out most experiments. M.E. gave helpful insights and discussion.

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Correspondence to Masamichi Imajo or Eisuke Nishida.

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The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 A picture showing a mouse whose intestine was tied with nylon string and injected with the transfection solution during iGT.

Supplementary Figure 2 Establishment and characterization of iGT.

(a) Cy3-labeled siRNAs were introduced into the small intestine as in Fig. 1g–j (3 h after iGT). Low magnification images of the small intestine transfected with Cy3-siRNA. (b) 293T cells were transfected with an expression plasmid for DsRed (red) by using HVJ-E. Cells were treated with DMSO or Roscovitine (40 μM) for 3 days from 1 day before transfection.

Supplementary Figure 3 Phenotypic analysis of the YAP/TAZ-knockdown intestinal epithelium.

(a) Representative images of mouse intestinal crypt organoids (red arrowheads) cultured for 4 days in the presence of either DMSO or 20 μM of verteporfin (VP). In control (DMSO) samples, many large organoids developed. Treatment with verteporfin markedly suppressed the growth of organoids and, by 4 days, most organoids were collapsed. Scale bar: 100 μm. (b,c) Staining for chromogranin A (b) and lysozyme (c) in the small intestine transfected with control siRNAs or YAP/TAZ siRNAs. The YAP/TAZ double-knockdown did not affect the numbers of enteroendocrine cells and Paneth cells. Scale bars: 50 μm.

Supplementary Figure 4 Phenotypic analysis of the intestinal epithelium expressing a dominant negative form of TEAD4 (TEAD-EnR).

(ac) An expression plasmid for TEAD4-EnR or a control plasmid was introduced into the intestinal epithelium. Scale bars: 50 μm. Staining for cleaved caspase-3 (a), lysozyme (b), and chromogranin A (c) showed that the TEAD4-EnR expression did not affect the numbers of apoptotic cells (a, red arrowheads), Paneth cells (b, green), or enteroendocrine cells (c, red arrowheads).

Supplementary Figure 5 Microarray analysis of the gene expression pattern regulated by YAP/TAZ, and co-immunoprecipitation of purified YAP and Klf4.

(a,b) Expression profiles of Paneth cell-specific genes (a) and genes which have been shown to regulate differentiation into goblet cells (b). The relative mRNA levels of each gene under four different conditions (siGFP, siYAP/siTAZ, shLacZ, and shYAP/shTAZ) are shown. The results show that the YAP/TAZ double-knockdown did not significantly affect the expression of these genes. (c) Expression profiles of β-catenin-dependent upregulated genes. (d) The percentages of the β-catenin-dependent upregulated genes and the other genes whose expression levels in the YAP/TAZ-knockdown epithelium were increased or decreased by more than 1.5-fold, as compared to control tissues, are shown. (e) The Klf4 mRNA levels in the control or the YAP/TAZ-knockdown tissues. (f) His-Klf4, GST-YAP, and/or GST-GFP were mixed and subjected to immunoprecipitation with anti-Klf4 antibody. GST-YAP, but not GST-GFP, was coprecipitated with His-Klf4. (g) Immunoblotting of lysates from the mouse small intestine transfected with expression plasmids for the indicated proteins. (h) (left) Immunoblotting of lysates from 293T cells, which were transfected with a control plasmid or an expression plasmid for either the full-length or the truncated form (151-504) of human YAP, with an anti-YAP antibody. Arrows indicate the bands of the full-length or the truncated form (151-504) of YAP. Note the presence of the truncated, shorter fragments of YAP (asterisks). (right) Immunoblotting of lysates from the mouse small intestine with an anti-YAP antibody. An arrow indicates the band of full-length mouse YAP. Note the presence of the truncated, shorter fragments of YAP (asterisk).

Supplementary Figure 6 Schematic representation of roles of YAP/TAZ in renewal of the intestinal epithelium.

YAP/TAZ function as a co-activator of TEAD transcription factors in crypt cells, especially in stem cells in which the expression levels of TEADs are high, and promote proliferation of these cells. Upon being destined for differentiation into the secretory lineage, YAP/TAZ cooperate with Klf4 to promote expression of genes, which promote differentiation into goblet cells (Muc2, Atoh1, etc.), in early common secretory progenitor cells and/or in late progenitor cells that are already specified into the goblet cell lineage. In addition, the YAP/TAZ-Klf4 complex also plays a role in promoting expression of a fraction of the enterocytic genes (Alpi, Efnb1, etc.) in absorptive progenitor cells.

Supplementary Figure 7 Uncropped scans of key western blots and DNA gel electrophoresis.

Supplementary information

Supplementary Information

Supplementary Information (PDF 692 kb)

Supplementary Table 1

A list of the YAP/TAZ-dependent upregulated genes. (XLSX 40 kb)

Supplementary Table 2

A list of the ISC signature genes whose expression levels are decreased by the YAP/TAZ double-knockdown. (XLSX 13 kb)

Supplementary Table 3

Gene ontology analyses of the YAP/TAZ-dependent upregulated genes bound by YAP and/or Klf4. (XLSX 14 kb)

Supplementary Table 4

Statistics source data. (XLSX 13 kb)

Supplementary Table 5

Sequences of primers used in this study. (XLSX 13 kb)

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Imajo, M., Ebisuya, M. & Nishida, E. Dual role of YAP and TAZ in renewal of the intestinal epithelium. Nat Cell Biol 17, 7–19 (2015). https://doi.org/10.1038/ncb3084

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