One diagnostic feature of craniosynostosis syndromes is mandibular dysgenesis. Using three mouse models of Apert, Crouzon and Pfeiffer craniosynostosis syndromes, we investigated how embryonic development of the mandible is affected by fibroblast growth factor receptor 2 (Fgfr2) mutations. Quantitative analysis of skeletal form at birth revealed differences in mandibular morphology between mice carrying Fgfr2 mutations and their littermates that do not carry the mutations. Murine embryos with the mutations associated with Apert syndrome in humans (Fgfr2^+/S252W and Fgfr2^+/P253R ) showed an increase in the size of the osteogenic anlagen and Meckel's cartilage (MC). Changes in the microarchitecture and mineralization of the developing mandible were visualized using histological staining. The mechanism for mandibular dysgenesis in the Apert Fgfr2^+/S252W mouse resulting in the most severe phenotypic effects was further analyzed in detail and found to occur to a lesser degree in the other craniosynostosis mouse models. Laser capture microdissection and RNA-seq analysis revealed transcriptomic changes in mandibular bone at embryonic day 16.5 (E16.5), highlighting increased expression of genes related to osteoclast differentiation and dysregulated genes active in bone mineralization. Increased osteoclastic activity was corroborated by TRAP assay and in situ hybridization of Csf1r and Itgb3 Upregulated expression of Enpp1 and Ank was validated in the mandible of Fgfr2^+/S252W embryos, and found to result in elevated inorganic pyrophosphate concentration. Increased proliferation of osteoblasts in the mandible and chondrocytes forming MC was identified in Fgfr2^+/S252W embryos at E12.5. These findings provide evidence that FGFR2 gain-of-function mutations differentially affect cartilage formation and intramembranous ossification of dermal bone, contributing to mandibular dysmorphogenesis in craniosynostosis syndromes.This article has an associated First Person interview with the joint first authors of the paper.

中文翻译：

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下颌畸形是由于FGFR2相关颅突神经病小鼠中异常的胚胎成骨作用引起的。

颅突神经综合征的诊断特征之一是下颌发育不全。使用Apert，Crouzon和Pfeiffer颅突神经综合征的三种小鼠模型，我们调查了下颌骨的胚胎发育如何受到成纤维细胞生长因子受体2（Fgfr2）突变的影响。出生时骨骼形态的定量分析显示，携带Fgfr2突变的小鼠与不携带该突变的同窝小鼠的下颌形态不同。具有人类Apert综合征相关突变的鼠胚（Fgfr2 ^{+ / S252W}和Fgfr2 ^{+ / P253R}）显示成骨性胶原蛋白和Meckel软骨（MC）的大小增加。使用组织学染色可观察到发育中的下颌骨的微结构和矿化变化。进一步详细分析了Apert Fgfr2 ^{+ / S252W}小鼠中导致最严重的表型效应的下颌发育不全的机制，并发现在其他颅前突病小鼠模型中发生的程度较小。激光捕获显微切割和RNA-seq分析揭示了在胚胎第16.5天（E16.5）下颌骨的转录组变化，突显了与破骨细胞分化相关的基因表达增加以及活跃在骨矿化中的基因失调。通过TRAP测定和原位证实了破骨细胞活性的提高Csf1r和Itgb3的杂交在Fgfr2 ^{+ / S252W}胚胎的下颌骨中验证了Enpp1和Ank的上调表达，并发现其导致无机焦磷酸盐浓度升高。在E12.5处的Fgfr2 ^{+ / S252W}胚胎中鉴定出形成MC的下颌骨和软骨细胞中成骨细胞增殖的增加。这些发现提供了证据，表明FGFR2功能获得突变差异地影响真皮骨的软骨形成和膜内骨化，导致颅突神经综合征的下颌畸形发生。本文与第一作者共同进行了采访。