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Beyond the closed suture in apert syndrome mouse models: evidence of primary effects of FGFR2 signaling on facial shape at birth.

ABSTRACT: Apert syndrome is a congenital disorder caused mainly by two neighboring mutations on fibroblast growth factor receptor 2 (FGFR2). Premature closure of the coronal suture is commonly considered the identifying and primary defect triggering or preceding the additional cranial malformations of Apert phenotype. Here we use two transgenic mouse models of Apert syndrome, Fgfr2(+/S252W) and Fgfr2(+/P253R), to explore variation in cranial phenotypes in newborn (P0) mice. Results show that the facial skeleton is the most affected region of the cranium. Coronal suture patency shows marked variation that is not strongly correlated with skull dysmorphology. The craniofacial effects of the FGFR2 mutations are similar, but Fgfr2(+/S252W) mutant mice display significantly more severe dysmorphology localized to the posterior palate. Our results demonstrate that coronal suture closure is neither the primary nor the sole locus of skull dysmorphology in these mouse models for Apert syndrome, but that the face is also primarily affected.

SUBMITTER: Martinez-Abadias N

PROVIDER: S-EPMC2965208 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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Beyond the closed suture in apert syndrome mouse models: evidence of primary effects of FGFR2 signaling on facial shape at birth.

Martínez-Abadías Neus N Percival Christopher C Aldridge Kristina K Hill Cheryl A CA Ryan Timothy T Sirivunnabood Satama S Wang Yingli Y Jabs Ethylin Wang EW Richtsmeier Joan T JT

Developmental dynamics : an official publication of the American Association of Anatomists 20101101 11

Apert syndrome is a congenital disorder caused mainly by two neighboring mutations on fibroblast growth factor receptor 2 (FGFR2). Premature closure of the coronal suture is commonly considered the identifying and primary defect triggering or preceding the additional cranial malformations of Apert phenotype. Here we use two transgenic mouse models of Apert syndrome, Fgfr2(+/S252W) and Fgfr2(+/P253R), to explore variation in cranial phenotypes in newborn (P0) mice. Results show that the facial sk ...[more]

PMID: 20842696

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Project description: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.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 PKCalpha 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.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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Beyond the closed suture in apert syndrome mouse models: evidence of primary effects of FGFR2 signaling on facial shape at birth.

Publications

Beyond the closed suture in apert syndrome mouse models: evidence of primary effects of FGFR2 signaling on facial shape at birth.

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