MRTF-A gain-of-function in mice impairs homeostatic renewal of the intestinal epithelium.
Cell Death Dis
; 14(9): 639, 2023 09 28.
Article
em En
| MEDLINE
| ID: mdl-37770456
ABSTRACT
The actin-regulated transcription factor MRTF-A represents a central relay in mechanotransduction and controls a subset of SRF-dependent target genes. However, gain-of-function studies in vivo are lacking. Here we characterize a conditional MRTF-A transgenic mouse model. While MRTF-A gain-of-function impaired embryonic development, induced expression of constitutively active MRTF-A provoked rapid hepatocyte ballooning and liver failure in adult mice. Specific expression in the intestinal epithelium caused an erosive architectural distortion, villus blunting, cryptal hyperplasia and colonic inflammation, resulting in transient weight loss. Organoids from transgenic mice repeatedly induced in vitro showed impaired self-renewal and defective cryptal compartments. Mechanistically, MRTF-A gain-of-function decreased proliferation and increased apoptosis, but did not induce fibrosis. MRTF-A targets including Acta2 and Pai-1 were induced, whereas markers of stem cells and differentiated cells were reduced. Our results suggest that activated MRTF-A in the intestinal epithelium shifts the balance between proliferation, differentiation and apoptosis.
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Base de dados:
MEDLINE
Assunto principal:
Transativadores
/
Mutação com Ganho de Função
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article