Differential regulation of β-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/β-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 β-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 β-catenin act as all-or-nothing regulators of Wnt-target gene expression. Blocking their interactions with β-catenin rapidly induces loss of IESCs and intestinal homeostasis. Conversely, N-terminally recruited co-factors fine-tune β-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/β-catenin output requires selective modulation of gene expression by transcriptional co-factors.

WNT as a Driver and Dependency in Cancer

“…2). The differential regulation of β-catenin by transcriptional cofactors preserves the narrow window of WNT activity to govern the fate of intestinal stem cells (44). Recently, Borrelli and colleagues (44) revealed that C-terminal coactivators of β-catenin act as a binary on/off switch for β-catenin transcription of WNT target genes, whereas N-terminal coactivators fine-tune β-catenin transcriptional output to the exact level required for proliferation and self-renewal of intestinal stem cells.…”

“…The differential regulation of β-catenin by transcriptional cofactors preserves the narrow window of WNT activity to govern the fate of intestinal stem cells (44). Recently, Borrelli and colleagues (44) revealed that C-terminal coactivators of β-catenin act as a binary on/off switch for β-catenin transcription of WNT target genes, whereas N-terminal coactivators fine-tune β-catenin transcriptional output to the exact level required for proliferation and self-renewal of intestinal stem cells. Rapid proliferation in the crypt results in a continuous movement of cells in an upward motion, pushing cells out of the crypt where they begin to differentiate into all intestinal epithelial lineages and finally end their life cycle by undergoing apical extrusion or shedding at the tip of the villus (45).…”

The interactions of Bcl9/Bcl9L with β-catenin and Pygopus promote breast cancer growth, invasion, and metastasis

“…The Bcl9/Bcl9L mutations also cause cardiac defects in zebrafish and mice by a β-catenin-dependent mechanism, yet the defective embryos still maintained a broad transcriptional activity of β-catenin [ 16 ]. Finally, the interaction of Bcl9/Bcl9L with β-catenin is important for the maintenance of intestinal epithelial stem cells by selectively modulating Wnt/β-catenin-mediated transcriptional output [ 17 ]. Yet, other transcription factors may also interact with Bcl9/Bcl9L and β-catenin to modulate their transcriptional output, as for example shown for the Tbx3-mediated promotion of colorectal cancer cell metastasis [ 18 ].…”

Loss of Nkd1 is epistatic to loss of Axin2 in regulating Wnt signaling

“…At the transcriptional level, Wnt target genes remain silent due to transcriptional repressors, such as Groucho, binding to Tcf/Lef transcription factors 14 .When Wnt signaling is on, a Wnt ligand binds its receptors Frizzled and Lipoprotein Receptor-Related Protein 5 and 6 (Lrp5/6) which recruits the cytoplasmic protein Dishevelled (Dvl) and the destruction complex to the membrane, resulting in the inactivation of the destruction complex 13 . Once this complex is deactivated, cytoplasmic levels of β-catenin stabilize allowing for the translocalization of β-catenin to the nucleus where it interacts with various coactivators to transcriptionally activate Wnt target genes 15 . Two of these Wnt target genes are axin2 and nkd1, which function as negative feedback regulators for the pathway 16,17 .Nkd1 is an antagonist in both the canonical and non-canonical Wnt signaling pathways [18][19][20] .…”