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

Daoud, Fatima LU ; Holmberg, Johan LU ; Alajbegovic, Azra LU ; Grossi, Mario LU ; Rippe, Catarina LU ; Swärd, Karl LU and Albinsson, Sebastian LU (2021) In Cellular and Molecular Gastroenterology and Hepatology 11(2). p.623-637
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 CreERT2 recombinase driven by the smooth muscle–specific myosin heavy chain promoter.

Results
Double-knockout of YAP/TAZ... (More)
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 CreERT2 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. (Less)
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author
; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
YAP1, TAZ, WWTR1, Muscarinic acetylcholine receptors, Constipation, Gastrointestinal, Contractility
in
Cellular and Molecular Gastroenterology and Hepatology
volume
11
issue
2
pages
623 - 637
publisher
Elsevier
external identifiers
  • pmid:32992050
  • scopus:85097454205
ISSN
2352-345X
DOI
10.1016/j.jcmgh.2020.09.014
language
English
LU publication?
yes
id
ac554c3d-3512-414f-b277-3e281175b9a7
date added to LUP
2021-12-05 10:55:52
date last changed
2022-05-24 18:22:56
@article{ac554c3d-3512-414f-b277-3e281175b9a7,
  abstract     = {{Background &amp; Aims<br/>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.<br/><br/>Methods<br/>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.<br/><br/>Results<br/>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.<br/><br/>Conclusions<br/>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.}},
  author       = {{Daoud, Fatima and Holmberg, Johan and Alajbegovic, Azra and Grossi, Mario and Rippe, Catarina and Swärd, Karl and Albinsson, Sebastian}},
  issn         = {{2352-345X}},
  keywords     = {{YAP1; TAZ; WWTR1; Muscarinic acetylcholine receptors; Constipation; Gastrointestinal; Contractility}},
  language     = {{eng}},
  number       = {{2}},
  pages        = {{623--637}},
  publisher    = {{Elsevier}},
  series       = {{Cellular and Molecular Gastroenterology and Hepatology}},
  title        = {{Inducible Deletion of YAP and TAZ in Adult Mouse Smooth Muscle Causes Rapid and Lethal Colonic Pseudo-Obstruction}},
  url          = {{http://dx.doi.org/10.1016/j.jcmgh.2020.09.014}},
  doi          = {{10.1016/j.jcmgh.2020.09.014}},
  volume       = {{11}},
  year         = {{2021}},
}