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Journal Article

MRTF-A gain-of-function in mice impairs homeostatic renewal of the intestinal epithelium

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Moser,  Markus
Fässler, Reinhard / Molecular Medicine, Max Planck Institute of Biochemistry, Max Planck Society;

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Citation

Singh, A. K., Rai, A., Weber, A., Gericke, M., Janssen, K.-P., Moser, M., et al. (2023). MRTF-A gain-of-function in mice impairs homeostatic renewal of the intestinal epithelium. Cell Death and Disease, 14(9): 639. doi:10.1038/s41419-023-06158-4.


Cite as: https://hdl.handle.net/21.11116/0000-000D-E4F1-1
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.