Inducible Deletion of YAP and TAZ in Adult Mouse Smooth Muscle Causes Rapid and Lethal Colonic Pseudo-Obstruction

• Published in: Cellular and molecular gastroenterology and hepatology Vol. 11; no. 2; pp. 623 - 637
• Main Authors: Daoud, Fatima, Holmberg, Johan, Alajbegovic, Azra, Grossi, Mario, Rippe, Catarina, Swärd, Karl, Albinsson, Sebastian
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-01-2021; Elsevier
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Animals; Basic Medicine; Cell and Molecular Biology; Cell- och molekylärbiologi; Colon - physiopathology; Colonic Pseudo-Obstruction - genetics; Colonic Pseudo-Obstruction - physiopathology; Constipation; Contractility; Disease Models, Animal; Female; Gastrointestinal; Gastrointestinal Motility - genetics; Humans; Male; Medical and Health Sciences; Medicin och hälsovetenskap; Medicinska och farmaceutiska grundvetenskaper; Mice; Mice, Knockout; Muscarinic; Muscarinic acetylcholine receptors; Muscle Contraction - genetics; Muscle, Smooth - physiopathology; Original Research; TAZ; TEAD; WWTR1; YAP-Signaling Proteins - genetics; YAP-Signaling Proteins - metabolism; YAP1; YAP1; WWTR1; GI; Muscarinic; mT/mG; SRF; Contractility; HRP; CCh; DAPI; mRNA; Ctrl; Gastrointestinal; Padj; TEAD; MRTF; Y/T KO; Constipation
• ISSN: 2352-345X; 2352-345X
• DOI: 10.1016/j.jcmgh.2020.09.014

YAP (Yap1) and TAZ (Wwtr1) are transcriptional co-activators and downstream effectors of the Hippo pathway, which play crucial roles in organ size control and cancer pathogenesis. Genetic deletion of YAP/TAZ has shown their critical importance for embryonic development of the heart, vasculature, and gastrointestinal mesenchyme. The aim of this study was to determine the functional role of YAP/TAZ in adult smooth muscle cells in vivo.
Because YAP and TAZ are mutually redundant, we used YAP/TAZ double-floxed mice crossed with mice that express tamoxifen-inducible CreERT2 recombinase driven by the smooth muscle–specific myosin heavy chain promoter.
Double-knockout of YAP/TAZ in adult smooth muscle causes lethality within 2 weeks, mainly owing to colonic pseudo-obstruction, characterized by severe distension and fecal impaction. RNA sequencing in colon and urinary bladder showed that smooth muscle markers and muscarinic receptors were down-regulated in the YAP/TAZ knockout. The same transcripts also correlated with YAP/TAZ in the human colon. Myograph experiments showed reduced contractility to depolarization by potassium chloride and a nearly abolished muscarinic contraction and spontaneous activity in colon rings of YAP/TAZ knockout.
YAP and TAZ in smooth muscle are guardians of colonic contractility and control expression of contractile proteins and muscarinic receptors. The knockout model has features of human chronic intestinal pseudo-obstruction and may be useful for studying this disease.
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