Severe intestinal obstruction on induced smooth muscle-specific ablation of the transcription factor SRF in adult mice

Abstract

Background & aims: SRF (Serum Response Factor), a widely expressed transcription factor, controls expression of mitogen-responsive and muscle-specific genes, thereby regulating the contractile actin microfilament. Genetic Srf deletion studies showed SRF to be indispensable for in vivo skeletal and cardiac muscle cell development. We now investigated for the first time in vivo SRF functions in smooth muscle cells of adult mice.

Methods: We conditionally deleted a floxed Srf allele (Srf(flex1)) in adult mice by inducible activation of the CreER(T2) recombinase expressed specifically in smooth muscle cells. Tamoxifen-induced CreER(T2) activity stimulated deletion of exon 1 coding sequences of Srf(flex1), thereby abolishing full-length SRF protein expression in adult smooth muscle cells of the analyzed organs: colon, bladder, and stomach.

Results: Smooth muscle cell-specific ablation of full-length SRF protein in adult mice showed impaired contraction of intestinal smooth muscle, resulting in defective peristalsis. Mutant mice died within 2 weeks of tamoxifen treatment, displaying clear symptoms of ileus paralyticus. Cultured primary SRF-deficient colon smooth muscle cells were viable, but displayed drastic structural alterations and elevated senescence, paralleled by degeneration of the actin microfilament and impaired expression of smooth muscle-specific genes.

Conclusions: SRF plays a vital role in the contractile activity and cytoskeletal architecture of adult smooth muscle cells and is therefore essential for physiologic functions of the gastrointestinal tract in vivo. Our mouse genetic model may resemble features of human chronic intestinal pseudo-obstruction.