Dynamic morphological changes in the skulls of mice mimicking human Apert syndrome resulting from gain‐of‐function mutation of FGFR2 (P253R)

Du, Xiaolan; Weng, Tujun; Sun, Qidi; Su, Nan; Chen, Zhi; Qi, Han; Jin, Ming; Liang, Yin; He, Qi; Chen, Lin

doi:10.1111/j.1469-7580.2010.01248.x

Cited by 13 publications

(16 citation statements)

References 17 publications

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“…The correspondence between Apert syndrome mouse models and human patients with Apert syndrome has been demonstrated at the morphological, histological and molecular levels (Chen et al, 2003; Wang et al, 2005; Wang et al, 2010; Holmes et al, 2009; Aldridge et al, 2010; Du et al, 2010; Martínez-Abadías et al, 2010; Martínez-Abadías et al, 2011), validating the use of large experimentally controlled samples of mouse models to elucidate the complex etiology of Apert syndrome.…”

Section: Introductionmentioning

confidence: 81%

From shape to cells: mouse models reveal mechanisms altering palate development in Apert syndrome

Martínez‐Abadías

Holmes

Pankratz

et al. 2013

Disease Models &Amp; Mechanisms

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SUMMARYApert syndrome is a congenital disorder characterized by severe skull malformations and caused by one of two missense mutations, S252W and P253R, on fibroblast growth factor receptor 2 (FGFR2). The molecular bases underlying differential Apert syndrome phenotypes are still poorly understood and it is unclear why cleft palate is more frequent in patients carrying the S252W mutation. Taking advantage of Apert syndrome mouse models, we performed a novel combination of morphometric, histological and immunohistochemical analyses to precisely quantify distinct palatal phenotypes in Fgfr2+/S252W and Fgfr2+/P253R mice. We localized regions of differentially altered FGF signaling and assessed local cell patterns to establish a baseline for understanding the differential effects of these two Fgfr2 mutations. Palatal suture scoring and comparative 3D shape analysis from high resolution μCT images of 120 newborn mouse skulls showed that Fgfr2+/S252W mice display relatively more severe palate dysmorphologies, with contracted and more separated palatal shelves, a greater tendency to fuse the maxillary-palatine sutures and aberrant development of the inter-premaxillary suture. These palatal defects are associated with suture-specific patterns of abnormal cellular proliferation, differentiation and apoptosis. The posterior region of the developing palate emerges as a potential target for therapeutic strategies in clinical management of cleft palate in Apert syndrome patients.

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Section: Introductionmentioning

confidence: 81%

From shape to cells: mouse models reveal mechanisms altering palate development in Apert syndrome

Martínez‐Abadías

Holmes

Pankratz

et al. 2013

Disease Models &Amp; Mechanisms

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“…Furthermore, it's noticed that the phenotypes of each mutant strain just partially resembled the skull malformation of EIIa-253 mice, suggesting that the malformation of specific tissues partially contributed to dysmorphogenesis of skull of AS mice (Fig. 7E)16, 21, 36, 37, and that the maldevelopment of AS head is caused by the combined effects of abnormal development of calvarias, cranial base, brain and other tissues (Fig. 7D).…”

Section: Resultsmentioning

confidence: 98%

“…In previous reports, Apert syndrome mouse models with ubiquitous expression of mutant FGFR2 generated using EIIa-Cre (such as EIIa-Fgfr2 +/P253R, abbreviated as EIIa-253) exhibited smaller body size, shorter cranial dimensions along the rostrocaudal axis and broader breadth of the frontal bone than wild-type littermates 10, 12, 16. In this study, Col2a1-253 mice showed normal life span with normal body size and AS-like skull dysmorphology compared with wild-type mice.…”

Section: Resultsmentioning

confidence: 99%

“…There are few comparative genetic analyses of the differential roles of calvarias, cranial base and brain in the pathogenesis of the skull malformation in AS using mouse models with tissue-specific activation of mutant FGFR210, 12, 16, 19. Also we don't know whether there is direct effect of mutant FGFR2 on the brain development.…”

Section: Discussionmentioning

confidence: 99%

“…Generally, these mouse models showed global skull phenotypes similar to that in Apert patients including dome-shaped skulls, underdeveloped midface, premature fusion of cranial base synchondrosis, malformed brain and brachycephaly, 10, 14 etc. Quantitative analyses revealed that the skulls of Fgfr2 +⁄P253R mice were shortened along the rostrocaudal (RC) direction, especially in their face15, but the breadth along the mediolateral (ML) axis of the frontal bone and the neurocranium were increased 16.…”

Section: Introductionmentioning

confidence: 99%

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Deformed Skull Morphology Is Caused by the Combined Effects of the Maldevelopment of Calvarias, Cranial Base and Brain in FGFR2-P253R Mice Mimicking Human Apert Syndrome

Luo¹,

Xie²,

Xu³

et al. 2017

Int. J. Biol. Sci.

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Apert syndrome (AS) is a common genetic syndrome in humans characterized with craniosynostosis. Apert patients and mouse models showed abnormalities in sutures, cranial base and brain, that may all be involved in the pathogenesis of skull malformation of Apert syndrome. To distinguish the differential roles of these components of head in the pathogenesis of the abnormal skull morphology of AS, we generated mouse strains specifically expressing mutant FGFR2 in chondrocytes, osteoblasts, and progenitor cells of central nervous system (CNS) by crossing Fgfr2+/P253R-Neo mice with Col2a1-Cre, Osteocalcin-Cre (OC-Cre), and Nestin-Cre mice, respectively. We then quantitatively analyzed the skull and brain morphology of these mutant mice by micro-CT and micro-MRI using Euclidean distance matrix analysis (EDMA). Skulls of Col2a1-Fgfr2+/P253R mice showed Apert syndrome-like dysmorphology, such as shortened skull dimensions along the rostrocaudal axis, shortened nasal bone, and evidently advanced ossification of cranial base synchondroses. The OC-Fgfr2+/P253R mice showed malformation in face at 8-week stage. Nestin-Fgfr2+/P253R mice exhibited increased dorsoventral height and rostrocaudal length on the caudal skull and brain at 8 weeks. Our study indicates that the abnormal skull morphology of AS is caused by the combined effects of the maldevelopment in calvarias, cranial base, and brain tissue. These findings further deepen our knowledge about the pathogenesis of the abnormal skull morphology of AS, and provide new clues for the further analyses of skull phenotypes and clinical management of AS.

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Reduces Bone Mass as in Human Apert Syndrome

Zhou

Liu

et al. 2013

American J of Med Genetics Pt A

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Apert syndrome is a common craniosynostosis caused by gain-of-function missense mutations of fibroblast growth factor receptor 2 (FGFR2). Mice with the FGFR2 S252W mutation can elucidate the mechanism by which the human Apert syndrome phenotypes arise. However, many studies have focused on mutant skull and long bone malformation, only few studies have focused on mandible changes. Bone formation and micro-architecture between 28- and 56-day-old mutant mice and controls were compared to investigate the changes in the mandibular micro-architecture caused by the Fgfr2(S252W/+) mutation to provide a basis for exploring the pathogenesis and therapeutic measures of human Apert syndrome. Fgfr2(S252W/+) mutant mice were established, and their general characteristics, including weight, naso-anal length, and calcium and phosphate content in serum and bone were tested. Calcein labeling, tartrate-resistant acid phosphatase staining and toluidine blue staining were used to detect osteoblast and osteoclast activities. H&E staining and micro-CT detection were used to test micro-architecture changes. The changes in mineral apposition rate and micro-architecture of the Fgfr2(S252W/+) mice were statistically significant; however, the magnitude of the micro-architecture became less with age. The Fgfr2(S252W/+) mutation may retard mandibular bone formation, decreased bone volume, and compromised skeletal architecture by regulating both osteoblastogenesis and osteoclastogenesis.

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Dynamic morphological changes in the skulls of mice mimicking human Apert syndrome resulting from gain‐of‐function mutation of FGFR2 (P253R)

Cited by 13 publications

References 17 publications

From shape to cells: mouse models reveal mechanisms altering palate development in Apert syndrome

From shape to cells: mouse models reveal mechanisms altering palate development in Apert syndrome

Deformed Skull Morphology Is Caused by the Combined Effects of the Maldevelopment of Calvarias, Cranial Base and Brain in FGFR2-P253R Mice Mimicking Human Apert Syndrome

Reduces Bone Mass as in Human Apert Syndrome

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