Differential regulation of ?-catenin-mediated transcription via N- and C-terminal co-factors governs identity of murine intestinal epithelial stem cells.

ABSTRACT: The homeostasis of the gut epithelium relies upon continuous renewal and proliferation of crypt-resident intestinal epithelial stem cells (IESCs). Wnt/?-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 ?-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 ?-catenin act as all-or-nothing regulators of Wnt-target gene expression. Blocking their interactions with ?-catenin rapidly induces loss of IESCs and intestinal homeostasis. Conversely, N-terminally recruited co-factors fine-tune ?-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/?-catenin output requires selective modulation of gene expression by transcriptional co-factors.

SUBMITTER: Borrelli C 

PROVIDER: S-EPMC7921392 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature