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Msx1 haploinsufficiency modifies the Pax9-deficient cardiovascular phenotype

BACKGROUND: Successful embryogenesis relies on the coordinated interaction between genes and tissues. The transcription factors Pax9 and Msx1 genetically interact during mouse craniofacial morphogenesis, and mice deficient for either gene display abnormal tooth and palate development. Pax9 is expres...

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Autores principales: Khasawneh, Ramada R., Kist, Ralf, Queen, Rachel, Hussain, Rafiqul, Coxhead, Jonathan, Schneider, Jürgen E., Mohun, Timothy J., Zaffran, Stéphane, Peters, Heiko, Phillips, Helen M., Bamforth, Simon D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8493722/
https://www.ncbi.nlm.nih.gov/pubmed/34615475
http://dx.doi.org/10.1186/s12861-021-00245-5
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author Khasawneh, Ramada R.
Kist, Ralf
Queen, Rachel
Hussain, Rafiqul
Coxhead, Jonathan
Schneider, Jürgen E.
Mohun, Timothy J.
Zaffran, Stéphane
Peters, Heiko
Phillips, Helen M.
Bamforth, Simon D.
author_facet Khasawneh, Ramada R.
Kist, Ralf
Queen, Rachel
Hussain, Rafiqul
Coxhead, Jonathan
Schneider, Jürgen E.
Mohun, Timothy J.
Zaffran, Stéphane
Peters, Heiko
Phillips, Helen M.
Bamforth, Simon D.
author_sort Khasawneh, Ramada R.
collection PubMed
description BACKGROUND: Successful embryogenesis relies on the coordinated interaction between genes and tissues. The transcription factors Pax9 and Msx1 genetically interact during mouse craniofacial morphogenesis, and mice deficient for either gene display abnormal tooth and palate development. Pax9 is expressed specifically in the pharyngeal endoderm at mid-embryogenesis, and mice deficient for Pax9 on a C57Bl/6 genetic background also have cardiovascular defects affecting the outflow tract and aortic arch arteries giving double-outlet right ventricle, absent common carotid arteries and interruption of the aortic arch. RESULTS: In this study we have investigated both the effect of a different genetic background and Msx1 haploinsufficiency on the presentation of the Pax9-deficient cardiovascular phenotype. Compared to mice on a C57Bl/6 background, congenic CD1-Pax9(–/–) mice displayed a significantly reduced incidence of outflow tract defects but aortic arch defects were unchanged. Pax9(–/–) mice with Msx1 haploinsufficiency, however, have a reduced incidence of interrupted aortic arch, but more cases with cervical origins of the right subclavian artery and aortic arch, than seen in Pax9(–/–) mice. This alteration in arch artery defects was accompanied by a rescue in third pharyngeal arch neural crest cell migration and smooth muscle cell coverage of the third pharyngeal arch arteries. Although this change in phenotype could theoretically be compatible with post-natal survival, using tissue-specific inactivation of Pax9 to maintain correct palate development whilst inducing the cardiovascular defects was unable to prevent postnatal death in the mutant mice. Hyoid bone and thyroid cartilage formation were abnormal in Pax9(–/–) mice. CONCLUSIONS: Msx1 haploinsufficiency mitigates the arch artery defects in Pax9(–/–) mice, potentially by maintaining the survival of the 3rd arch artery through unimpaired migration of neural crest cells to the third pharyngeal arches. With the neural crest cell derived hyoid bone and thyroid cartilage also being defective in Pax9(–/–) mice, we speculate that the pharyngeal endoderm is a key signalling centre that impacts on neural crest cell behaviour highlighting the ability of cells in different tissues to act synergistically or antagonistically during embryo development. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12861-021-00245-5.
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spelling pubmed-84937222021-10-06 Msx1 haploinsufficiency modifies the Pax9-deficient cardiovascular phenotype Khasawneh, Ramada R. Kist, Ralf Queen, Rachel Hussain, Rafiqul Coxhead, Jonathan Schneider, Jürgen E. Mohun, Timothy J. Zaffran, Stéphane Peters, Heiko Phillips, Helen M. Bamforth, Simon D. BMC Dev Biol Research BACKGROUND: Successful embryogenesis relies on the coordinated interaction between genes and tissues. The transcription factors Pax9 and Msx1 genetically interact during mouse craniofacial morphogenesis, and mice deficient for either gene display abnormal tooth and palate development. Pax9 is expressed specifically in the pharyngeal endoderm at mid-embryogenesis, and mice deficient for Pax9 on a C57Bl/6 genetic background also have cardiovascular defects affecting the outflow tract and aortic arch arteries giving double-outlet right ventricle, absent common carotid arteries and interruption of the aortic arch. RESULTS: In this study we have investigated both the effect of a different genetic background and Msx1 haploinsufficiency on the presentation of the Pax9-deficient cardiovascular phenotype. Compared to mice on a C57Bl/6 background, congenic CD1-Pax9(–/–) mice displayed a significantly reduced incidence of outflow tract defects but aortic arch defects were unchanged. Pax9(–/–) mice with Msx1 haploinsufficiency, however, have a reduced incidence of interrupted aortic arch, but more cases with cervical origins of the right subclavian artery and aortic arch, than seen in Pax9(–/–) mice. This alteration in arch artery defects was accompanied by a rescue in third pharyngeal arch neural crest cell migration and smooth muscle cell coverage of the third pharyngeal arch arteries. Although this change in phenotype could theoretically be compatible with post-natal survival, using tissue-specific inactivation of Pax9 to maintain correct palate development whilst inducing the cardiovascular defects was unable to prevent postnatal death in the mutant mice. Hyoid bone and thyroid cartilage formation were abnormal in Pax9(–/–) mice. CONCLUSIONS: Msx1 haploinsufficiency mitigates the arch artery defects in Pax9(–/–) mice, potentially by maintaining the survival of the 3rd arch artery through unimpaired migration of neural crest cells to the third pharyngeal arches. With the neural crest cell derived hyoid bone and thyroid cartilage also being defective in Pax9(–/–) mice, we speculate that the pharyngeal endoderm is a key signalling centre that impacts on neural crest cell behaviour highlighting the ability of cells in different tissues to act synergistically or antagonistically during embryo development. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12861-021-00245-5. BioMed Central 2021-10-06 /pmc/articles/PMC8493722/ /pubmed/34615475 http://dx.doi.org/10.1186/s12861-021-00245-5 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Khasawneh, Ramada R.
Kist, Ralf
Queen, Rachel
Hussain, Rafiqul
Coxhead, Jonathan
Schneider, Jürgen E.
Mohun, Timothy J.
Zaffran, Stéphane
Peters, Heiko
Phillips, Helen M.
Bamforth, Simon D.
Msx1 haploinsufficiency modifies the Pax9-deficient cardiovascular phenotype
title Msx1 haploinsufficiency modifies the Pax9-deficient cardiovascular phenotype
title_full Msx1 haploinsufficiency modifies the Pax9-deficient cardiovascular phenotype
title_fullStr Msx1 haploinsufficiency modifies the Pax9-deficient cardiovascular phenotype
title_full_unstemmed Msx1 haploinsufficiency modifies the Pax9-deficient cardiovascular phenotype
title_short Msx1 haploinsufficiency modifies the Pax9-deficient cardiovascular phenotype
title_sort msx1 haploinsufficiency modifies the pax9-deficient cardiovascular phenotype
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8493722/
https://www.ncbi.nlm.nih.gov/pubmed/34615475
http://dx.doi.org/10.1186/s12861-021-00245-5
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