Differential regulation of ß-catenin-mediated transcription via N- and C-terminal co-factors governs identity of murine intestinal epithelial stem cells.
Nat Commun
; 12(1): 1368, 2021 03 01.
Article
em En
| MEDLINE
| ID: mdl-33649334
ABSTRACT
The homeostasis of the gut epithelium relies upon continuous renewal and proliferation of crypt-resident intestinal epithelial stem cells (IESCs). Wnt/ß-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 ß-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 ß-catenin act as all-or-nothing regulators of Wnt-target gene expression. Blocking their interactions with ß-catenin rapidly induces loss of IESCs and intestinal homeostasis. Conversely, N-terminally recruited co-factors fine-tune ß-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/ß-catenin output requires selective modulation of gene expression by transcriptional co-factors.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Células-Tronco
/
Fatores de Transcrição
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Transcrição Gênica
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Beta Catenina
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Mucosa Intestinal
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article