Cargando…
Reduced dosage of β-catenin provides significant rescue of cardiac outflow tract anomalies in a Tbx1 conditional null mouse model of 22q11.2 deletion syndrome
The 22q11.2 deletion syndrome (22q11.2DS; velo-cardio-facial syndrome; DiGeorge syndrome) is a congenital anomaly disorder in which haploinsufficiency of TBX1, encoding a T-box transcription factor, is the major candidate for cardiac outflow tract (OFT) malformations. Inactivation of Tbx1 in the ant...
Autores principales: | , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2017
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5386301/ https://www.ncbi.nlm.nih.gov/pubmed/28346476 http://dx.doi.org/10.1371/journal.pgen.1006687 |
_version_ | 1782520744942501888 |
---|---|
author | Racedo, Silvia E. Hasten, Erica Lin, Mingyan Devakanmalai, Gnanapackiam Sheela Guo, Tingwei Ozbudak, Ertugrul M. Cai, Chen-Leng Zheng, Deyou Morrow, Bernice E. |
author_facet | Racedo, Silvia E. Hasten, Erica Lin, Mingyan Devakanmalai, Gnanapackiam Sheela Guo, Tingwei Ozbudak, Ertugrul M. Cai, Chen-Leng Zheng, Deyou Morrow, Bernice E. |
author_sort | Racedo, Silvia E. |
collection | PubMed |
description | The 22q11.2 deletion syndrome (22q11.2DS; velo-cardio-facial syndrome; DiGeorge syndrome) is a congenital anomaly disorder in which haploinsufficiency of TBX1, encoding a T-box transcription factor, is the major candidate for cardiac outflow tract (OFT) malformations. Inactivation of Tbx1 in the anterior heart field (AHF) mesoderm in the mouse results in premature expression of pro-differentiation genes and a persistent truncus arteriosus (PTA) in which septation does not form between the aorta and pulmonary trunk. Canonical Wnt/β-catenin has major roles in cardiac OFT development that may act upstream of Tbx1. Consistent with an antagonistic relationship, we found the opposite gene expression changes occurred in the AHF in β-catenin loss of function embryos compared to Tbx1 loss of function embryos, providing an opportunity to test for genetic rescue. When both alleles of Tbx1 and one allele of β-catenin were inactivated in the Mef2c-AHF-Cre domain, 61% of them (n = 34) showed partial or complete rescue of the PTA defect. Upregulated genes that were oppositely changed in expression in individual mutant embryos were normalized in significantly rescued embryos. Further, β-catenin was increased in expression when Tbx1 was inactivated, suggesting that there may be a negative feedback loop between canonical Wnt and Tbx1 in the AHF to allow the formation of the OFT. We suggest that alteration of this balance may contribute to variable expressivity in 22q11.2DS. |
format | Online Article Text |
id | pubmed-5386301 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-53863012017-05-03 Reduced dosage of β-catenin provides significant rescue of cardiac outflow tract anomalies in a Tbx1 conditional null mouse model of 22q11.2 deletion syndrome Racedo, Silvia E. Hasten, Erica Lin, Mingyan Devakanmalai, Gnanapackiam Sheela Guo, Tingwei Ozbudak, Ertugrul M. Cai, Chen-Leng Zheng, Deyou Morrow, Bernice E. PLoS Genet Research Article The 22q11.2 deletion syndrome (22q11.2DS; velo-cardio-facial syndrome; DiGeorge syndrome) is a congenital anomaly disorder in which haploinsufficiency of TBX1, encoding a T-box transcription factor, is the major candidate for cardiac outflow tract (OFT) malformations. Inactivation of Tbx1 in the anterior heart field (AHF) mesoderm in the mouse results in premature expression of pro-differentiation genes and a persistent truncus arteriosus (PTA) in which septation does not form between the aorta and pulmonary trunk. Canonical Wnt/β-catenin has major roles in cardiac OFT development that may act upstream of Tbx1. Consistent with an antagonistic relationship, we found the opposite gene expression changes occurred in the AHF in β-catenin loss of function embryos compared to Tbx1 loss of function embryos, providing an opportunity to test for genetic rescue. When both alleles of Tbx1 and one allele of β-catenin were inactivated in the Mef2c-AHF-Cre domain, 61% of them (n = 34) showed partial or complete rescue of the PTA defect. Upregulated genes that were oppositely changed in expression in individual mutant embryos were normalized in significantly rescued embryos. Further, β-catenin was increased in expression when Tbx1 was inactivated, suggesting that there may be a negative feedback loop between canonical Wnt and Tbx1 in the AHF to allow the formation of the OFT. We suggest that alteration of this balance may contribute to variable expressivity in 22q11.2DS. Public Library of Science 2017-03-27 /pmc/articles/PMC5386301/ /pubmed/28346476 http://dx.doi.org/10.1371/journal.pgen.1006687 Text en © 2017 Racedo et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Racedo, Silvia E. Hasten, Erica Lin, Mingyan Devakanmalai, Gnanapackiam Sheela Guo, Tingwei Ozbudak, Ertugrul M. Cai, Chen-Leng Zheng, Deyou Morrow, Bernice E. Reduced dosage of β-catenin provides significant rescue of cardiac outflow tract anomalies in a Tbx1 conditional null mouse model of 22q11.2 deletion syndrome |
title | Reduced dosage of β-catenin provides significant rescue of cardiac outflow tract anomalies in a Tbx1 conditional null mouse model of 22q11.2 deletion syndrome |
title_full | Reduced dosage of β-catenin provides significant rescue of cardiac outflow tract anomalies in a Tbx1 conditional null mouse model of 22q11.2 deletion syndrome |
title_fullStr | Reduced dosage of β-catenin provides significant rescue of cardiac outflow tract anomalies in a Tbx1 conditional null mouse model of 22q11.2 deletion syndrome |
title_full_unstemmed | Reduced dosage of β-catenin provides significant rescue of cardiac outflow tract anomalies in a Tbx1 conditional null mouse model of 22q11.2 deletion syndrome |
title_short | Reduced dosage of β-catenin provides significant rescue of cardiac outflow tract anomalies in a Tbx1 conditional null mouse model of 22q11.2 deletion syndrome |
title_sort | reduced dosage of β-catenin provides significant rescue of cardiac outflow tract anomalies in a tbx1 conditional null mouse model of 22q11.2 deletion syndrome |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5386301/ https://www.ncbi.nlm.nih.gov/pubmed/28346476 http://dx.doi.org/10.1371/journal.pgen.1006687 |
work_keys_str_mv | AT racedosilviae reduceddosageofbcateninprovidessignificantrescueofcardiacoutflowtractanomaliesinatbx1conditionalnullmousemodelof22q112deletionsyndrome AT hastenerica reduceddosageofbcateninprovidessignificantrescueofcardiacoutflowtractanomaliesinatbx1conditionalnullmousemodelof22q112deletionsyndrome AT linmingyan reduceddosageofbcateninprovidessignificantrescueofcardiacoutflowtractanomaliesinatbx1conditionalnullmousemodelof22q112deletionsyndrome AT devakanmalaignanapackiamsheela reduceddosageofbcateninprovidessignificantrescueofcardiacoutflowtractanomaliesinatbx1conditionalnullmousemodelof22q112deletionsyndrome AT guotingwei reduceddosageofbcateninprovidessignificantrescueofcardiacoutflowtractanomaliesinatbx1conditionalnullmousemodelof22q112deletionsyndrome AT ozbudakertugrulm reduceddosageofbcateninprovidessignificantrescueofcardiacoutflowtractanomaliesinatbx1conditionalnullmousemodelof22q112deletionsyndrome AT caichenleng reduceddosageofbcateninprovidessignificantrescueofcardiacoutflowtractanomaliesinatbx1conditionalnullmousemodelof22q112deletionsyndrome AT zhengdeyou reduceddosageofbcateninprovidessignificantrescueofcardiacoutflowtractanomaliesinatbx1conditionalnullmousemodelof22q112deletionsyndrome AT morrowbernicee reduceddosageofbcateninprovidessignificantrescueofcardiacoutflowtractanomaliesinatbx1conditionalnullmousemodelof22q112deletionsyndrome |