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Cong Wang, Julia Yu Fong Chang, Chaofeng Yang, Yanqing Huang, Junchen Liu, Pan You, Wallace L McKeehan, Fen Wang, Xiaokun Li
College of Pharmacy, Wenzhou Medical College, Wenzhou, Zhejiang 325000, China.
J Biol Chem. 2013 Jul 26;288(30):22174-83. doi: 10.1074/jbc.M113.463620. Epub 2013 Jun 10.
Cleft palate is a common congenital birth defect. The fibroblast growth factor (FGF) family has been shown to be important for palatogenesis, which elicits the regulatory functions by activating the FGF receptor tyrosine kinase. Mutations in Fgf or Fgfr are associated with cleft palate. To date, most mechanistic studies on FGF signaling in palate development have focused on FGFR2 in the epithelium. Although Fgfr1 is expressed in the cranial neural crest (CNC)-derived palate mesenchyme and Fgfr1 mutations are associated with palate defects, how FGFR1 in palate mesenchyme regulates palatogenesis is not well understood. Here, we reported that by using Wnt1(Cre) to delete Fgfr1 in neural crest cells led to cleft palate, cleft lip, and other severe craniofacial defects. Detailed analyses revealed that loss-of-function mutations in Fgfr1 did not abrogate patterning of CNC cells in palate shelves. However, it upset cell signaling in the frontofacial areas, delayed cell proliferation in both epithelial and mesenchymal compartments, prevented palate shelf elevation, and compromised palate shelf fusion. This is the first report revealing how FGF signaling in CNC cells regulates palatogenesis.
腭裂是一种常见的先天性出生缺陷。成纤维细胞生长因子（FGF）家族已被证明对腭发生很重要，它通过激活 FGF 受体酪氨酸激酶来发挥调节作用。Fgf 或 Fgfr 的突变与腭裂有关。迄今为止，腭发育中 FGF 信号转导的大多数机制研究都集中在腭上皮细胞中的 FGFR2 上。尽管 Fgfr1 在颅神经嵴（CNC）衍生的腭间质中表达，并且 Fgfr1 突变与腭裂缺陷有关，但腭间质中的 FGFR1 如何调节腭发生还不是很清楚。在这里，我们报道了使用 Wnt1(Cre) 来删除神经嵴细胞中的 Fgfr1 会导致腭裂、唇裂和其他严重的颅面缺陷。详细分析表明，Fgfr1 的功能丧失突变并没有取消腭褶中 CNC 细胞的模式形成。然而，它扰乱了额面部的细胞信号，延迟了上皮和间质两个部分的细胞增殖，阻止了腭褶的抬高，并损害了腭褶的融合。这是第一个揭示 CNC 细胞中的 FGF 信号如何调节腭发生的报告。
