Activation of p38 MAPK pathway in the skull abnormalities of Apert syndrome Fgfr2+P253R mice

Yingli Wang, Miao Sun, Victoria L. Uhlhorn, Xueyan Zhou, Inga Peter, Neus Martinez-Abadias, Cheryl A. Hill, Christopher J. Percival, Joan T. Richtsmeier, David L. Huso, Ethylin Wang Jabs

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Abstract

Background. Apert syndrome is characterized by craniosynostosis and limb abnormalities and is primarily caused by FGFR2 +/P253R and +/S252W mutations. The former mutation is present in approximately one third whereas the latter mutation is present in two-thirds of the patients with this condition. We previously reported an inbred transgenic mouse model with the Fgfr2 +/S252W mutation on the C57BL/6J background for Apert syndrome. Here we present a mouse model for the Fgfr2+/P253R mutation. Results. We generated inbred Fgfr2 +/P253R mice on the same C56BL/6J genetic background and analyzed their skeletal abnormalities. 3D micro-CT scans of the skulls of the Fgfr2 +/P253R mice revealed that the skull length was shortened with the length of the anterior cranial base significantly shorter than that of the Fgfr2+/S252W mice at P0. The Fgfr2+/P253R mice presented with synostosis of the coronal suture and proximate fronts with disorganized cellularity in sagittal and lambdoid sutures. Abnormal osteogenesis and proliferation were observed at the developing coronal suture and long bones of the Fgfr2+/P253R mice as in the Fgfr2+/S252W mice. Activation of mitogen-activated protein kinases (MAPK) was observed in the Fgfr2+/P253R neurocranium with an increase in phosphorylated p38 as well as ERK1/2, whereas phosphorylated AKT and PKC were not obviously changed as compared to those of wild-type controls. There were localized phenotypic and molecular variations among individual embryos with different mutations and among those with the same mutation. Conclusions. Our in vivo studies demonstrated that the Fgfr2 +/P253R mutation resulted in mice with cranial features that resemble those of the Fgfr2+/S252W mice and human Apert syndrome. Activated p38 in addition to the ERK1/2 signaling pathways may mediate the mutant neurocranial phenotype. Though Apert syndrome is traditionally thought to be a consistent phenotype, our results suggest localized and regional variations in the phenotypes that characterize Apert syndrome.

Original languageEnglish (US)
Article number22
JournalBMC Developmental Biology
Volume10
DOIs
StatePublished - Mar 11 2010

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Acrocephalosyndactylia
p38 Mitogen-Activated Protein Kinases
Skull
Mutation
Sutures
Phenotype
Synostosis
Craniosynostoses
MAP Kinase Signaling System
Skull Base
Mitogen-Activated Protein Kinases
Osteogenesis
Transgenic Mice
Embryonic Structures
Extremities
Bone and Bones

All Science Journal Classification (ASJC) codes

  • Developmental Biology

Cite this

Wang, Y., Sun, M., Uhlhorn, V. L., Zhou, X., Peter, I., Martinez-Abadias, N., ... Jabs, E. W. (2010). Activation of p38 MAPK pathway in the skull abnormalities of Apert syndrome Fgfr2+P253R mice. BMC Developmental Biology, 10, [22]. https://doi.org/10.1186/1471-213X-10-22
Wang, Yingli ; Sun, Miao ; Uhlhorn, Victoria L. ; Zhou, Xueyan ; Peter, Inga ; Martinez-Abadias, Neus ; Hill, Cheryl A. ; Percival, Christopher J. ; Richtsmeier, Joan T. ; Huso, David L. ; Jabs, Ethylin Wang. / Activation of p38 MAPK pathway in the skull abnormalities of Apert syndrome Fgfr2+P253R mice. In: BMC Developmental Biology. 2010 ; Vol. 10.
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abstract = "Background. Apert syndrome is characterized by craniosynostosis and limb abnormalities and is primarily caused by FGFR2 +/P253R and +/S252W mutations. The former mutation is present in approximately one third whereas the latter mutation is present in two-thirds of the patients with this condition. We previously reported an inbred transgenic mouse model with the Fgfr2 +/S252W mutation on the C57BL/6J background for Apert syndrome. Here we present a mouse model for the Fgfr2+/P253R mutation. Results. We generated inbred Fgfr2 +/P253R mice on the same C56BL/6J genetic background and analyzed their skeletal abnormalities. 3D micro-CT scans of the skulls of the Fgfr2 +/P253R mice revealed that the skull length was shortened with the length of the anterior cranial base significantly shorter than that of the Fgfr2+/S252W mice at P0. The Fgfr2+/P253R mice presented with synostosis of the coronal suture and proximate fronts with disorganized cellularity in sagittal and lambdoid sutures. Abnormal osteogenesis and proliferation were observed at the developing coronal suture and long bones of the Fgfr2+/P253R mice as in the Fgfr2+/S252W mice. Activation of mitogen-activated protein kinases (MAPK) was observed in the Fgfr2+/P253R neurocranium with an increase in phosphorylated p38 as well as ERK1/2, whereas phosphorylated AKT and PKC were not obviously changed as compared to those of wild-type controls. There were localized phenotypic and molecular variations among individual embryos with different mutations and among those with the same mutation. Conclusions. Our in vivo studies demonstrated that the Fgfr2 +/P253R mutation resulted in mice with cranial features that resemble those of the Fgfr2+/S252W mice and human Apert syndrome. Activated p38 in addition to the ERK1/2 signaling pathways may mediate the mutant neurocranial phenotype. Though Apert syndrome is traditionally thought to be a consistent phenotype, our results suggest localized and regional variations in the phenotypes that characterize Apert syndrome.",
author = "Yingli Wang and Miao Sun and Uhlhorn, {Victoria L.} and Xueyan Zhou and Inga Peter and Neus Martinez-Abadias and Hill, {Cheryl A.} and Percival, {Christopher J.} and Richtsmeier, {Joan T.} and Huso, {David L.} and Jabs, {Ethylin Wang}",
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Wang, Y, Sun, M, Uhlhorn, VL, Zhou, X, Peter, I, Martinez-Abadias, N, Hill, CA, Percival, CJ, Richtsmeier, JT, Huso, DL & Jabs, EW 2010, 'Activation of p38 MAPK pathway in the skull abnormalities of Apert syndrome Fgfr2+P253R mice', BMC Developmental Biology, vol. 10, 22. https://doi.org/10.1186/1471-213X-10-22

Activation of p38 MAPK pathway in the skull abnormalities of Apert syndrome Fgfr2+P253R mice. / Wang, Yingli; Sun, Miao; Uhlhorn, Victoria L.; Zhou, Xueyan; Peter, Inga; Martinez-Abadias, Neus; Hill, Cheryl A.; Percival, Christopher J.; Richtsmeier, Joan T.; Huso, David L.; Jabs, Ethylin Wang.

In: BMC Developmental Biology, Vol. 10, 22, 11.03.2010.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Activation of p38 MAPK pathway in the skull abnormalities of Apert syndrome Fgfr2+P253R mice

AU - Wang, Yingli

AU - Sun, Miao

AU - Uhlhorn, Victoria L.

AU - Zhou, Xueyan

AU - Peter, Inga

AU - Martinez-Abadias, Neus

AU - Hill, Cheryl A.

AU - Percival, Christopher J.

AU - Richtsmeier, Joan T.

AU - Huso, David L.

AU - Jabs, Ethylin Wang

PY - 2010/3/11

Y1 - 2010/3/11

N2 - Background. Apert syndrome is characterized by craniosynostosis and limb abnormalities and is primarily caused by FGFR2 +/P253R and +/S252W mutations. The former mutation is present in approximately one third whereas the latter mutation is present in two-thirds of the patients with this condition. We previously reported an inbred transgenic mouse model with the Fgfr2 +/S252W mutation on the C57BL/6J background for Apert syndrome. Here we present a mouse model for the Fgfr2+/P253R mutation. Results. We generated inbred Fgfr2 +/P253R mice on the same C56BL/6J genetic background and analyzed their skeletal abnormalities. 3D micro-CT scans of the skulls of the Fgfr2 +/P253R mice revealed that the skull length was shortened with the length of the anterior cranial base significantly shorter than that of the Fgfr2+/S252W mice at P0. The Fgfr2+/P253R mice presented with synostosis of the coronal suture and proximate fronts with disorganized cellularity in sagittal and lambdoid sutures. Abnormal osteogenesis and proliferation were observed at the developing coronal suture and long bones of the Fgfr2+/P253R mice as in the Fgfr2+/S252W mice. Activation of mitogen-activated protein kinases (MAPK) was observed in the Fgfr2+/P253R neurocranium with an increase in phosphorylated p38 as well as ERK1/2, whereas phosphorylated AKT and PKC were not obviously changed as compared to those of wild-type controls. There were localized phenotypic and molecular variations among individual embryos with different mutations and among those with the same mutation. Conclusions. Our in vivo studies demonstrated that the Fgfr2 +/P253R mutation resulted in mice with cranial features that resemble those of the Fgfr2+/S252W mice and human Apert syndrome. Activated p38 in addition to the ERK1/2 signaling pathways may mediate the mutant neurocranial phenotype. Though Apert syndrome is traditionally thought to be a consistent phenotype, our results suggest localized and regional variations in the phenotypes that characterize Apert syndrome.

AB - Background. Apert syndrome is characterized by craniosynostosis and limb abnormalities and is primarily caused by FGFR2 +/P253R and +/S252W mutations. The former mutation is present in approximately one third whereas the latter mutation is present in two-thirds of the patients with this condition. We previously reported an inbred transgenic mouse model with the Fgfr2 +/S252W mutation on the C57BL/6J background for Apert syndrome. Here we present a mouse model for the Fgfr2+/P253R mutation. Results. We generated inbred Fgfr2 +/P253R mice on the same C56BL/6J genetic background and analyzed their skeletal abnormalities. 3D micro-CT scans of the skulls of the Fgfr2 +/P253R mice revealed that the skull length was shortened with the length of the anterior cranial base significantly shorter than that of the Fgfr2+/S252W mice at P0. The Fgfr2+/P253R mice presented with synostosis of the coronal suture and proximate fronts with disorganized cellularity in sagittal and lambdoid sutures. Abnormal osteogenesis and proliferation were observed at the developing coronal suture and long bones of the Fgfr2+/P253R mice as in the Fgfr2+/S252W mice. Activation of mitogen-activated protein kinases (MAPK) was observed in the Fgfr2+/P253R neurocranium with an increase in phosphorylated p38 as well as ERK1/2, whereas phosphorylated AKT and PKC were not obviously changed as compared to those of wild-type controls. There were localized phenotypic and molecular variations among individual embryos with different mutations and among those with the same mutation. Conclusions. Our in vivo studies demonstrated that the Fgfr2 +/P253R mutation resulted in mice with cranial features that resemble those of the Fgfr2+/S252W mice and human Apert syndrome. Activated p38 in addition to the ERK1/2 signaling pathways may mediate the mutant neurocranial phenotype. Though Apert syndrome is traditionally thought to be a consistent phenotype, our results suggest localized and regional variations in the phenotypes that characterize Apert syndrome.

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