Basic–Alimentary TractSevere Intestinal Obstruction on Induced Smooth Muscle–Specific Ablation of the Transcription Factor SRF in Adult Mice
Section snippets
Generation of Adult SM-Specific Srf Mutant Mice
Srfflex116 and SM-CreERT2(ki)/wt17 mice were bred for Srfflex1 homozygosity and Cre transgene heterozygosity, using a mixed genetic background (C57BL/6N-NMRI).
Srfflex1/flex1:SMCreERT2/wt mice were used in all experiments, when treated with tamoxifen for induced recombination, were referred to as mutant or SRF knockout mice. Cre-mediated recombination of the Srfflex1 allele generates the Srflx deletion allele.16 Control mice include tamoxifen-treated Srfflex1/wt:SMCreERT2/wt or Srfflex1/flex1
Generation of Mice with SMC-Specific Disruption of the Srf Gene
To investigate the role of SRF in murine adult SMCs, we used the conditional Srfflex1 allele harboring loxP sites flanking the coding sequence of Srf exon 1, which is essential for nuclear localization and CArG box–specific DNA binding of SRF.16 Srfflex1 mice were bred with transgenic mice expressing a tamoxifen-inducible Cre recombinase, CreERT2, under the control of the SM-specific SM22α promoter [SM-CreERT2(ki)].17 Thus, SM-CreERT2–mediated deletion of the floxed Srf exon 1 should occur only
Discussion
To determine in vivo the role of the transcription factor SRF in SMCs, we mutated by inducible, time-controlled recombination the floxed Srfflex1 allele specifically in SMCs of adult mice. Depletion of SRF in SMCs led to dilation and impaired contraction of GI organs, resulting in defective peristalsis in vivo and death within 2 weeks. Autopsy of mutant mice revealed clear symptoms of ileus paralyticus, and both toxicity28 and malnutrition can be assumed as the probable cause of death.
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2024, American Journal of PathologyRole of smooth muscle YAP and TAZ in protection against phenotypic modulation, inflammation, and aneurysm development
2022, Biochemical PharmacologyCitation Excerpt :This forced us to euthanize all mice 12 days after tamoxifen injection to comply with national ethical guidelines. The gastrointestinal phenotype, referred to as colonic pseudo-obstruction, is essentially identical to that seen in SMC-specific and inducible Srf-knockout mice [110–112]. Mechanistically, we found that YAP/TAZ deletion reduced numerous contractile proteins and SMC markers along with two receptors for acetylcholine that are critical for gastrointestinal motility [52].
Neuropilin 2 Is a Novel Regulator of Distal Colon Contractility
2022, American Journal of PathologyCitation Excerpt :In those studies, inducible smooth muscle–specific loss of serum response factor was associated with intestinal obstruction and death within approximately 2 weeks. Contractile activity of colonic tissue from serum response factor deleted mice was significantly diminished compared with that in intact mice and was associated with a marked reduction in smooth muscle–specific contractile proteins, including α-smooth muscle actin, smooth muscle–myosin heavy chain, and calponin.39,40 In our study, however, no significant differences were noted in the level of SM contractile proteins, suggesting alternative mechanisms are driving the increase in contractile force observed in our analysis.
Inducible Deletion of YAP and TAZ in Adult Mouse Smooth Muscle Causes Rapid and Lethal Colonic Pseudo-Obstruction
2021, Cellular and Molecular Gastroenterology and HepatologyCitation Excerpt :In the latter regard, the phenotype of Y/T KO mice is similar to inducible and smooth muscle–specific deletion of SRF in adult mice. Adult SRF mutants die within 16–28 days, with distension of the cecum and colon, reduced GI transit, and reduced muscarinic contraction.19–21 This is caused primarily by reduced levels of contractile proteins.
Supported by the Deutsche Forschungsgemeinschaft (SFB446/B7 and NO 120/12-2) and the Fonds der Chemischen Industrie (to M.A. and A.N.).
All authors declare that they have no conflict of interest to disclose.