Dataset Information

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

ABSTRACT:

Background & aims

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.

Methods

Because YAP and TAZ are mutually redundant, we used YAP/TAZ double-floxed mice crossed with mice that express tamoxifen-inducible CreER^T2 recombinase driven by the smooth muscle-specific myosin heavy chain promoter.

Results

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.

Conclusions

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.

SUBMITTER: Daoud F

PROVIDER: S-EPMC7806867 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Publications

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

Daoud Fatima F Holmberg Johan J Alajbegovic Azra A Grossi Mario M Rippe Catarina C Swärd Karl K Albinsson Sebastian S

Cellular and molecular gastroenterology and hepatology 20200928 2

<h4>Background & aims</h4>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.<h4>Methods</h4>Because YAP and TAZ a ...[more]

PMID: 32992050

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Project description:ObjectivesPneumatosis intestinalis is a rare condition with subserosal or submucosal gas-filled cysts of the gastrointestinal tract. It is often associated with acute mesenteric ischemia, but also non-ischemic causes are described.Case presentationA 27-year-old male patient with severe congenital spastic tetraparesis presented to the emergency room with fever and reduced general condition. The patient was hypotonic and tachycardic, had a fever up to 39.7 °C and reduced peripheral oxygen saturation. The laboratory analyses revealed leukocytosis (16.7 G/L) and elevated CRP (162 mg/L).The patient was admitted to the intensive care unit (ICU) for invasive ventilator treatment because of global respiratory insufficiency and antibiotic therapy due to acute pneumonia and severe acute respiratory distress syndrome (ARDS). In addition, he suffered from colonic pseudo-obstruction but with persistent stool passage. After pulmonary recovery, he was transferred to the normal ward of internal medicine, but signs of colonic pseudo-obstruction were still present.Under therapy with diatrizoic acid and neostigmine, the abdomen was less distended, and the patient had regular bowel movements. After four days, the patient developed sudden acute abdominal pain and suffered sudden pulseless electrical activity. Immediate cardiopulmonary resuscitation was provided. After the return of spontaneous circulation, the patient underwent computed tomography (CT) and was re-admitted to the ICU. The CT scan showed massive dilatation of the colon, including pneumatosis coli, extensive gas formation within the mesenteric veins and arteries, including massive portal gas in the liver, the splenic vein, the renal veins, and disruption of abdominal aortic perfusion. The patient was then first presented for surgical evaluation, but due to futile prognosis, treatment was ceased on the ICU.ConclusionsIn conclusion, colonic pseudo-obstruction might have led to colonic necrosis and consecutive massive gas formation within the mesenteric vessels. Therefore, intestinal passage should be restored as soon as possible to avoid possible mortality.

Dataset Information

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

Background & aims

Methods

Results

Conclusions

Publications

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

Similar Datasets

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