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Craniofacial divergence by distinct prenatal growth patterns in Fgfr2 mutant mice

BACKGROUND: Differences in cranial morphology arise due to changes in fundamental cell processes like migration, proliferation, differentiation and cell death driven by genetic programs. Signaling between fibroblast growth factors (FGFs) and their receptors (FGFRs) affect these processes during head...

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Autores principales: Motch Perrine, Susan M, Cole, Theodore M, Martínez-Abadías, Neus, Aldridge, Kristina, Jabs, Ethylin Wang, Richtsmeier, Joan T
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4101838/
https://www.ncbi.nlm.nih.gov/pubmed/24580805
http://dx.doi.org/10.1186/1471-213X-14-8
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author Motch Perrine, Susan M
Cole, Theodore M
Martínez-Abadías, Neus
Aldridge, Kristina
Jabs, Ethylin Wang
Richtsmeier, Joan T
author_facet Motch Perrine, Susan M
Cole, Theodore M
Martínez-Abadías, Neus
Aldridge, Kristina
Jabs, Ethylin Wang
Richtsmeier, Joan T
author_sort Motch Perrine, Susan M
collection PubMed
description BACKGROUND: Differences in cranial morphology arise due to changes in fundamental cell processes like migration, proliferation, differentiation and cell death driven by genetic programs. Signaling between fibroblast growth factors (FGFs) and their receptors (FGFRs) affect these processes during head development and mutations in FGFRs result in congenital diseases including FGFR-related craniosynostosis syndromes. Current research in model organisms focuses primarily on how these mutations change cell function local to sutures under the hypothesis that prematurely closing cranial sutures contribute to skull dysmorphogenesis. Though these studies have provided fundamentally important information contributing to the understanding of craniosynostosis conditions, knowledge of changes in cell function local to the sutures leave change in overall three-dimensional cranial morphology largely unexplained. Here we investigate growth of the skull in two inbred mouse models each carrying one of two gain-of-function mutations in FGFR2 on neighboring amino acids (S252W and P253R) that in humans cause Apert syndrome, one of the most severe FGFR-related craniosynostosis syndromes. We examine late embryonic skull development and suture patency in Fgfr2 Apert syndrome mice between embryonic day 17.5 and birth and quantify the effects of these mutations on 3D skull morphology, suture patency and growth. RESULTS: We show in mice what studies in humans can only infer: specific cranial growth deviations occur prenatally and worsen with time in organisms carrying these FGFR2 mutations. We demonstrate that: 1) distinct skull morphologies of each mutation group are established by E17.5; 2) cranial suture patency patterns differ between mice carrying these mutations and their unaffected littermates; 3) the prenatal skull grows differently in each mutation group; and 4) unique Fgfr2-related cranial morphologies are exacerbated by late embryonic growth patterns. CONCLUSIONS: Our analysis of mutation-driven changes in cranial growth provides a previously missing piece of knowledge necessary for explaining variation in emergent cranial morphologies and may ultimately be helpful in managing human cases carrying these same mutations. This information is critical to the understanding of craniofacial development, disease and evolution and may contribute to the evaluation of incipient therapeutic strategies.
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spelling pubmed-41018382014-07-18 Craniofacial divergence by distinct prenatal growth patterns in Fgfr2 mutant mice Motch Perrine, Susan M Cole, Theodore M Martínez-Abadías, Neus Aldridge, Kristina Jabs, Ethylin Wang Richtsmeier, Joan T BMC Dev Biol Research Article BACKGROUND: Differences in cranial morphology arise due to changes in fundamental cell processes like migration, proliferation, differentiation and cell death driven by genetic programs. Signaling between fibroblast growth factors (FGFs) and their receptors (FGFRs) affect these processes during head development and mutations in FGFRs result in congenital diseases including FGFR-related craniosynostosis syndromes. Current research in model organisms focuses primarily on how these mutations change cell function local to sutures under the hypothesis that prematurely closing cranial sutures contribute to skull dysmorphogenesis. Though these studies have provided fundamentally important information contributing to the understanding of craniosynostosis conditions, knowledge of changes in cell function local to the sutures leave change in overall three-dimensional cranial morphology largely unexplained. Here we investigate growth of the skull in two inbred mouse models each carrying one of two gain-of-function mutations in FGFR2 on neighboring amino acids (S252W and P253R) that in humans cause Apert syndrome, one of the most severe FGFR-related craniosynostosis syndromes. We examine late embryonic skull development and suture patency in Fgfr2 Apert syndrome mice between embryonic day 17.5 and birth and quantify the effects of these mutations on 3D skull morphology, suture patency and growth. RESULTS: We show in mice what studies in humans can only infer: specific cranial growth deviations occur prenatally and worsen with time in organisms carrying these FGFR2 mutations. We demonstrate that: 1) distinct skull morphologies of each mutation group are established by E17.5; 2) cranial suture patency patterns differ between mice carrying these mutations and their unaffected littermates; 3) the prenatal skull grows differently in each mutation group; and 4) unique Fgfr2-related cranial morphologies are exacerbated by late embryonic growth patterns. CONCLUSIONS: Our analysis of mutation-driven changes in cranial growth provides a previously missing piece of knowledge necessary for explaining variation in emergent cranial morphologies and may ultimately be helpful in managing human cases carrying these same mutations. This information is critical to the understanding of craniofacial development, disease and evolution and may contribute to the evaluation of incipient therapeutic strategies. BioMed Central 2014-02-28 /pmc/articles/PMC4101838/ /pubmed/24580805 http://dx.doi.org/10.1186/1471-213X-14-8 Text en Copyright © 2014 Motch Perrine et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Motch Perrine, Susan M
Cole, Theodore M
Martínez-Abadías, Neus
Aldridge, Kristina
Jabs, Ethylin Wang
Richtsmeier, Joan T
Craniofacial divergence by distinct prenatal growth patterns in Fgfr2 mutant mice
title Craniofacial divergence by distinct prenatal growth patterns in Fgfr2 mutant mice
title_full Craniofacial divergence by distinct prenatal growth patterns in Fgfr2 mutant mice
title_fullStr Craniofacial divergence by distinct prenatal growth patterns in Fgfr2 mutant mice
title_full_unstemmed Craniofacial divergence by distinct prenatal growth patterns in Fgfr2 mutant mice
title_short Craniofacial divergence by distinct prenatal growth patterns in Fgfr2 mutant mice
title_sort craniofacial divergence by distinct prenatal growth patterns in fgfr2 mutant mice
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4101838/
https://www.ncbi.nlm.nih.gov/pubmed/24580805
http://dx.doi.org/10.1186/1471-213X-14-8
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