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.
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DOI：
10.1242/dmm.010397
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发表时间：
2013-05
影响因子：
4.3
通讯作者：
Richtsmeier JT
中科院分区：
文献类型：
--
作者：
Martínez-Abadías N;Holmes G;Pankratz T;Wang Y;Zhou X;Jabs EW;Richtsmeier JT
Apert综合征是一种以严重颅骨畸形为特征的先天性疾病，由成纤维细胞生长因子受体2（FGFR 2）上的两个错义突变S252W和P253R之一引起。差异Apert综合征表型的分子基础仍然知之甚少，也不清楚为什么腭裂在携带S252W突变的患者中更常见。利用Apert综合征小鼠模型，我们进行了一种新的组合的形态学，组织学和免疫组织化学分析，以精确定量不同的腭表型Fgfr 2 +/S252W和Fgfr 2 +/P253R小鼠。我们定位差异改变的FGF信号传导区域，并评估局部细胞模式，以建立理解这两种Fgfr 2突变差异效应的基线。对120个新生小鼠头骨的高分辨率μ CT图像进行腭缝评分和比较3D形状分析表明，Fgfr 2 +/S252W小鼠显示出相对更严重的腭畸形，腭架收缩和分离，上颌-腭缝融合的趋势更大，颌间前缝发育异常。这些腭部缺陷与异常细胞增殖、分化和凋亡的缝合特异性模式相关。在Apert综合征患者的腭裂临床治疗中，发育中的腭后部区域成为治疗策略的潜在目标。
Apert 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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DOI：
10.1242/dev.037689
发表时间：
2010-11
期刊：
Development (Cambridge, England)
影响因子：
--
作者：
Dorey K;Amaya E
通讯作者：
Amaya E
DOI：
10.1098/rspb.2007.1169
发表时间：
2008-01-07
影响因子：
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作者：
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影响因子：
10.5
作者：
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通讯作者：
Ornitz, DM
影响因子：
4.1
作者：
Chen, L;Li, D;Deng, CX
通讯作者：
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影响因子：
2.5
作者：
Aldridge, Kristina;Hill, Cheryl A.;Austin, Jordan R.;Percival, Christopher;Martinez-Abadias, Neus;Neuberger, Thomas;Wang, Yingli;Jabs, Ethylin Wang;Richtsmeier, Joan T.
通讯作者：
Richtsmeier, Joan T.