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

Costanza Borrelli, Tomas Valenta (), Kristina Handler, Karelia Vélez, Alessandra Gurtner, Giulia Moro, Atefeh Lafzi, Laura de Vargas Roditi, George Hausmann, Isabelle C. Arnold, Andreas E. Moor and Konrad Basler ()
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Costanza Borrelli: University of Zurich
Tomas Valenta: University of Zurich
Kristina Handler: Department of Biosystems Science and Engineering, ETH Zurich
Karelia Vélez: Department of Biosystems Science and Engineering, ETH Zurich
Alessandra Gurtner: University of Zurich
Giulia Moro: University of Zurich
Atefeh Lafzi: Department of Biosystems Science and Engineering, ETH Zurich
Laura de Vargas Roditi: Department of Biosystems Science and Engineering, ETH Zurich
George Hausmann: University of Zurich
Isabelle C. Arnold: University of Zurich
Andreas E. Moor: Department of Biosystems Science and Engineering, ETH Zurich
Konrad Basler: University of Zurich

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-21591-9

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