| First Author | Borrelli C | Year | 2021 |
| Journal | Nat Commun | Volume | 12 |
| Issue | 1 | Pages | 1368 |
| PubMed ID | 33649334 | Mgi Jnum | J:304888 |
| Mgi Id | MGI:6515133 | Doi | 10.1038/s41467-021-21591-9 |
| Citation | Borrelli C, et al. (2021) Differential regulation of beta-catenin-mediated transcription via N- and C-terminal co-factors governs identity of murine intestinal epithelial stem cells. Nat Commun 12(1):1368 |
| abstractText | The homeostasis of the gut epithelium relies upon continuous renewal and proliferation of crypt-resident intestinal epithelial stem cells (IESCs). Wnt/beta-catenin signaling is required for IESC maintenance, however, it remains unclear how this pathway selectively governs the identity and proliferative decisions of IESCs. Here, we took advantage of knock-in mice harboring transgenic beta-catenin alleles with mutations that specifically impair the recruitment of N- or C-terminal transcriptional co-factors. We show that C-terminally-recruited transcriptional co-factors of beta-catenin act as all-or-nothing regulators of Wnt-target gene expression. Blocking their interactions with beta-catenin rapidly induces loss of IESCs and intestinal homeostasis. Conversely, N-terminally recruited co-factors fine-tune beta-catenin's transcriptional output to ensure proper self-renewal and proliferative behaviour of IESCs. Impairment of N-terminal interactions triggers transient hyperproliferation of IESCs, eventually resulting in exhaustion of the self-renewing stem cell pool. IESC mis-differentiation, accompanied by unfolded protein response stress and immune infiltration, results in a process resembling aberrant "villisation" of intestinal crypts. Our data suggest that IESC-specific Wnt/beta-catenin output requires selective modulation of gene expression by transcriptional co-factors. |
