The primary site of the acrocephalic feature in Apert syndrome is a dwarf cranial base with accelerated chondrocytic differentiation due to aberrant activation of the FGFR2 signaling

Nakagawa, Masaki; Nuckolls, Glen H.; Wang, Xibin; Shum, Lillian; Seki, Yukie; Kawase, Tomoyuki; Takahashi, Kazuyuki; Nonaka, Kenichi; Takahashi, Ichiro; Noman, Arhab A.; Suzuki, Kenji; Slavkin, Harold C.

doi:10.1016/j.bone.2010.11.014

Cited by 28 publications

(34 citation statements)

References 35 publications

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“…FGFR2IIIc P253R mice carry the mutation identified in Apert syndrome, which leads to constitutive activation of FGFR2. The mutant mice have precocious ossification in the SOS at birth and subsequently in the ISS (Nagata et al 2011). This premature fusion of the cranial synchondroses is associated with accelerated maturation and hypertrophy of chondrocytes.…”

Section: Fgf Signalingmentioning

confidence: 99%

Developmental Regulation of the Growth Plate and Cranial Synchondrosis

Wei

Mishina

et al. 2016

J Dent Res

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Long bones and the cranial base are both formed through endochondral ossification. Elongation of long bones is primarily through the growth plate, which is a cartilaginous structure at the end of long bones made up of chondrocytes. Growth plate chondrocytes are organized in columns along the longitudinal axis of bone growth. The cranial base is the growth center of the neurocranium. Synchondroses, consisting of mirror-image growth plates, are critical for cranial base elongation and development. Over the last decade, considerable progress has been made in determining the roles of the parathyroid hormone-related protein, Indian hedgehog, fibroblast growth factor, bone morphogenetic protein, and Wnt signaling pathways in various aspects of skeletal development. Furthermore, recent evidence indicates the important role of the primary cilia signaling pathway in bone elongation. Here, we review the development of the growth plate and cranial synchondrosis and the regulation by the above-mentioned signaling pathways, highlighting the similarities and differences between these 2 structures.

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Section: Fgf Signalingmentioning

confidence: 99%

Developmental Regulation of the Growth Plate and Cranial Synchondrosis

Wei

Mishina

et al. 2016

J Dent Res

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“…S7), which, according to our fatemapping analysis, would be predicted to initiate within the primordial coronal suture at E11.0. This experimental strategy circumvents the possibility of targeting skeletogenic populations that do not express En1, thereby allowing us to address the longstanding question of whether Fgfr2 activation in the cranial base is a primary, albeit indirect, cause of coronal synostosis in AP syndrome (Wang et al, 2005;Nagata et al, 2010). Analysis of En1…”

Section: Research Articlementioning

confidence: 99%

Regulation of cranial morphogenesis and cell fate at the neural crest-mesoderm boundary by engrailed 1

et al. 2012

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SUMMARYThe characterization of mesenchymal progenitors is central to understanding development, postnatal pathology and evolutionary adaptability. The precise identity of the mesenchymal precursors that generate the coronal suture, an important structural boundary in mammalian skull development, remains unclear. We show in mouse that coronal suture progenitors originate from hedgehog-responsive cephalic paraxial mesoderm (Mes) cells, which migrate rapidly to a supraorbital domain and establish a unidirectional lineage boundary with neural crest (NeuC) mesenchyme. Lineage tracing reveals clonal and stereotypical expansion of supraorbital mesenchymal cells to form the coronal suture between E11.0 and E13.5. We identify engrailed 1 (En1) as a necessary regulator of cell movement and NeuC/Mes lineage boundary positioning during coronal suture formation. In addition, we provide genetic evidence that En1 functions upstream of fibroblast growth factor receptor 2 (Fgfr2) in regulating early calvarial osteogenic differentiation, and postulate that it plays an additional role in precluding premature osteogenic conversion of the sutural mesenchyme.

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“…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%

“…Individuals with AS are reported to have cartilaginous abnormalities in their cranial base, including premature fusion of the spheno-ethmoidal synchondrosis and the spheno-occipital synchondrosis, suggesting an important role of endochondral ossification in the skull malformation of AS 17, 18. Similarly, dysmorphology of the cranial base is one of the significant skeletal abnormalities in mice with ubiquitous or chondrocyte-specific expression of FGFR2 with Pro253Arg mutation19. Therefore, it is speculated that the disturbed cartilaginous development may also play an important role in the malformation of skulls of AS patients or AS mouse models.…”

Section: Introductionmentioning

confidence: 99%

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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The primary site of the acrocephalic feature in Apert syndrome is a dwarf cranial base with accelerated chondrocytic differentiation due to aberrant activation of the FGFR2 signaling

Cited by 28 publications

References 35 publications

Developmental Regulation of the Growth Plate and Cranial Synchondrosis

Developmental Regulation of the Growth Plate and Cranial Synchondrosis

Regulation of cranial morphogenesis and cell fate at the neural crest-mesoderm boundary by engrailed 1

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

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