Cargando…
Inducible Deletion of YAP and TAZ in Adult Mouse Smooth Muscle Causes Rapid and Lethal Colonic Pseudo-Obstruction
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...
Autores principales: | , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2020
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806867/ https://www.ncbi.nlm.nih.gov/pubmed/32992050 http://dx.doi.org/10.1016/j.jcmgh.2020.09.014 |
_version_ | 1783636618732634112 |
---|---|
author | Daoud, Fatima Holmberg, Johan Alajbegovic, Azra Grossi, Mario Rippe, Catarina Swärd, Karl Albinsson, Sebastian |
author_facet | Daoud, Fatima Holmberg, Johan Alajbegovic, Azra Grossi, Mario Rippe, Catarina Swärd, Karl Albinsson, Sebastian |
author_sort | Daoud, Fatima |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7806867 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-78068672021-01-22 Inducible Deletion of YAP and TAZ in Adult Mouse Smooth Muscle Causes Rapid and Lethal Colonic Pseudo-Obstruction Daoud, Fatima Holmberg, Johan Alajbegovic, Azra Grossi, Mario Rippe, Catarina Swärd, Karl Albinsson, Sebastian Cell Mol Gastroenterol Hepatol Original Research 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. Elsevier 2020-09-28 /pmc/articles/PMC7806867/ /pubmed/32992050 http://dx.doi.org/10.1016/j.jcmgh.2020.09.014 Text en © 2020 The Authors http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Original Research Daoud, Fatima Holmberg, Johan Alajbegovic, Azra Grossi, Mario Rippe, Catarina Swärd, Karl Albinsson, Sebastian Inducible Deletion of YAP and TAZ in Adult Mouse Smooth Muscle Causes Rapid and Lethal Colonic Pseudo-Obstruction |
title | Inducible Deletion of YAP and TAZ in Adult Mouse Smooth Muscle Causes Rapid and Lethal Colonic Pseudo-Obstruction |
title_full | Inducible Deletion of YAP and TAZ in Adult Mouse Smooth Muscle Causes Rapid and Lethal Colonic Pseudo-Obstruction |
title_fullStr | Inducible Deletion of YAP and TAZ in Adult Mouse Smooth Muscle Causes Rapid and Lethal Colonic Pseudo-Obstruction |
title_full_unstemmed | Inducible Deletion of YAP and TAZ in Adult Mouse Smooth Muscle Causes Rapid and Lethal Colonic Pseudo-Obstruction |
title_short | Inducible Deletion of YAP and TAZ in Adult Mouse Smooth Muscle Causes Rapid and Lethal Colonic Pseudo-Obstruction |
title_sort | inducible deletion of yap and taz in adult mouse smooth muscle causes rapid and lethal colonic pseudo-obstruction |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806867/ https://www.ncbi.nlm.nih.gov/pubmed/32992050 http://dx.doi.org/10.1016/j.jcmgh.2020.09.014 |
work_keys_str_mv | AT daoudfatima inducibledeletionofyapandtazinadultmousesmoothmusclecausesrapidandlethalcolonicpseudoobstruction AT holmbergjohan inducibledeletionofyapandtazinadultmousesmoothmusclecausesrapidandlethalcolonicpseudoobstruction AT alajbegovicazra inducibledeletionofyapandtazinadultmousesmoothmusclecausesrapidandlethalcolonicpseudoobstruction AT grossimario inducibledeletionofyapandtazinadultmousesmoothmusclecausesrapidandlethalcolonicpseudoobstruction AT rippecatarina inducibledeletionofyapandtazinadultmousesmoothmusclecausesrapidandlethalcolonicpseudoobstruction AT swardkarl inducibledeletionofyapandtazinadultmousesmoothmusclecausesrapidandlethalcolonicpseudoobstruction AT albinssonsebastian inducibledeletionofyapandtazinadultmousesmoothmusclecausesrapidandlethalcolonicpseudoobstruction |