The Myc 3'wnt-responsive element regulates homeostasis and regeneration in the mouse intestinal tract

The Wnt/β-catenin signaling pathway controls cellular proliferation in the intestines. In response to Wnt, β-catenin transits into the nucleus and associates with members of the T-cell factor (TCF) family of transcription factors. β-Catenin/TCF complexes bind Wnt responsive DNA elements (WREs) to activate target gene expression. The c-MYC proto-oncogene (MYC) is a direct target of β-catenin/TCF complexes. We recently identified the MYC 3'WRE, which maps 1.4-kb downstream from the MYC transcription stop site. To investigate the role of the Myc 3'WRE in the intestines, we generated a mouse model with a germ line deletion of this element. The intestinal architecture was largely preserved in knockout mice; however, removal of the Myc 3'WRE compromised the crypt microenvironment. In comparison to wild-type intestines, knockout intestines contained an increased number of proliferative cells and a reduced number of differentiated cells comprising both absorptive and secretory lineages. Using a model of colitis, we found that knockout colons repaired more rapidly during the recovery period of the protocol. These results indicate that regulation of MYC expression through the Myc 3= WRE contributes to intestinal homeostasis. Furthermore, our study implicates MYC as an important regulator of intestinal regeneration following injury.