Differential phenotypes in mice with smooth muscle-specific heterozygous versus homozygous deletion of Stk11.

Liver kinase B1 (Lkb1), encoded by the serine/threonine kinase gene STK11, functions as a critical tumor suppressor associated with Peutz-Jeghers syndrome (PJS). Previous studies have shown that mesenchymal-specific deletion of Stk11 promotes the development of PJS-like polyps in murine models, highlighting its essential role in mesenchymal homeostasis. In this study, we generated tamoxifen-inducible Stk11flox/flox;Myh11-Cre/ERT2 mice to achieve targeted deletion of Stk11 in mature smooth muscle cells (SMCs), allowing a comparative analysis of heterozygous versus homozygous loss-of-function phenotypes. We found that homozygous ablation of Stk11 in mature Myh11+ SMCs resulted in systemic arteriomegaly and extensive dilatation of gastrointestinal and genitourinary organs—including intestinal segments, gallbladder, ureters, and bladder. These structural abnormalities were associated with significant thinning of the muscularis propria layer and compromised tissue integrity. Interestingly, heterozygous deletion of Stk11 in mature Myh11+ SMCs fully recapitulated polyp formation characteristic of PJS, whereas complete knockout of Stk11 in these cells unexpectedly failed to induce gastrointestinal polyposis. Our results establish Stk11 as a fundamental regulator of both vascular and visceral SMC homeostasis. The genotype-dependent phenotypic divergence in SMC-specific Stk11 deficiency models underscores distinct mechanistic contributions to tissue-specific tumor suppression and PJS pathogenesis.