Inducible mouse model of chronic intestinal pseudo-obstruction by smooth muscle-specific inactivation of the SRF gene

Background & Aims: Serum response factor (SRF) regulates the expression of muscle genes and immediate early genes. We investigated the consequences of inactivating this transcription factor SRF in adult gastrointestinal smooth muscle cells. Methods: SRF-floxed mice were crossed with SMCreER(T2) (ki) mice expressing a tamoxifen-inducible recombinase in smooth muscle cells. Tamoxifen was injected into 12-week-old animals to activate the CreER(T2) and excise the SRF gene. Results: SRF was down-regulated in the smooth muscle cells of the gastrointestinal tract, urinary bladder, and aorta. The mutant mice developed severe dilation of the intestinal tract associated with food stasis and air-fluid levels in the lumen 13 days after tamoxifen treatment. Mutant mice displayed cachexia and died between days 13 and 22. The dilation was associated with a thinning of the muscularis propria and was also observed in the urinary bladder. Ex vivo colonic contraction induced by electric field stimulation and carbachol was impaired in the mutant mice before the occurrence of the dilation phenotype. The expression of several genes, including those encoding smooth muscle actin, the heavy chain of smooth muscle myosin, and smoothelin, was 60% to 70% lower in mutants than in controls, and mutants also had a lower F/G actin ratio. Conclusions: SRF plays a central role in maintaining visceral smooth muscle contractile function in adults. Mice with a smooth muscle cell-specific SRF mutation develop a severe motility disorder resembling chronic intestinal pseudo-obstruction in humans and may be used as an inducible model of this disorder.