Abstract
The human intestine is covered by epithelium, which is continuously replaced by new cells provided by stem cells located at the bottom of the glands. The maintenance of intestinal stem cells is supported by a niche which is composed of several signaling proteins including the Hippo pathway effectors YAP1/TAZ. The role of YAP1/TAZ in cell proliferation and regeneration is well documented but their involvement on the differentiation of intestinal epithelial cells is unclear. In the present study, the role of YAP1/TAZ on the differentiation of intestinal epithelial cells was investigated using the HT29 cell line, the only multipotent intestinal cell line available, with a combination of knockdown approaches. The expression of intestinal differentiation cell markers was tested by qPCR, Western blot, indirect immunofluorescence and electron microscopy analyses. The results show that TAZ is not expressed while the abolition of YAP1 expression led to a sharp increase in goblet and absorptive cell differentiation and reduction of some stem cell markers. Further studies using double knockdown experiments revealed that most of these effects resulting from YAP1 abolition are mediated by CDX2, a key intestinal cell transcription factor. In conclusion, our results indicate that YAP1/TAZ negatively regulate the differentiation of intestinal epithelial cells through the inhibition of CDX2 expression.
Highlights
The luminal surface of the mammalian intestine is covered by single layer of epithelial cells, which digest and absorb nutrients and form a protective layer against pathogens [1].The epithelium of the intestine has one of the highest turnover rates in the body, being continuously replaced by new cells provided by LGR5 positive crypt base columnar (CBC) stem cells [2,3,4]
The expression of Yes associated protein 1 (YAP1)/transcriptional co-activator with PDZ-binding motif (TAZ) protein was detected in the nucleus of some crypt cells located in the stem cell zone
These cells are located between the Paneth cells in which YAP1/TAZ protein was found below detectable levels in their nuclei (Figure 1 and Figure S1) in agreement with previous findings reporting an9,absence ofREVIEW
Summary
The luminal surface of the mammalian intestine is covered by single layer of epithelial cells, which digest and absorb nutrients and form a protective layer against pathogens [1].The epithelium of the intestine has one of the highest turnover rates in the body, being continuously replaced by new cells provided by LGR5 positive crypt base columnar (CBC) stem cells [2,3,4]. The luminal surface of the mammalian intestine is covered by single layer of epithelial cells, which digest and absorb nutrients and form a protective layer against pathogens [1]. Absorptive progenitors proliferate and give rise to the absorptive cells (enterocytes), which compose more than 80% of epithelial cells, while secretory progenitors have limited proliferation and differentiate into Paneth, goblet and enteroendocrine cells [7,8]. Enterocytes are simple columnar epithelial cells characterized by the brush border on their apical surface to increase the surface for digestion and absorption of nutrients. The main secretory cell type, goblet cells, produces highly glycosylated gel-forming mucins, MUC2 and trefoil factor 3 (TFF3), which limits bacterial access and stabilizes the mucus layer [12], while Paneth cells secret antimicrobial peptides including alpha defensins (DEFAs) and
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