The cellular and molecular etiology of the cleft secondary palate in Fgf10 mutant mice
The cellular and molecular etiology of the cleft secondary palate in Fgf10 mutant mice
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DOI：
10.1016/j.ydbio.2004.09.010
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发表时间：
2005-01-01
影响因子：
2.7
通讯作者：
Chen, YP
中科院分区：
文献类型：
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作者：
Alappat, SR;Zhang, ZY;Chen, YP
哺乳动物的腭发育取决于口源性上皮和颅神经嵴源性外间充质之间的相互作用。成纤维细胞生长因子 10 (FGF10) 是一种间充质信号因子，可通过组织-组织相互作用指导多个器官的形态发生。这与在 Fgf10(-/-) 小鼠中观察到的广泛的器官发育不全和发育不全一致。在这项研究中，我们报告了 Fgf10 纯合无效突变小鼠中存在大开的次级腭裂。在正常腭发育过程中，在 E 11.5 至 E 13.5 的腭间充质中检测到 Fgf10 转录本，并在腭架的前部和中部富集。在Fgf10(-/-)胚胎中，组织学分析显示，从E13.5开始，前部腭架与舌头异常粘连，中后部与下颌骨融合，这可能会阻止腭架正常抬高，导致腭裂。 TUNEL 和 BrdU 检测显示内侧边缘上皮 (MEE) 中细胞凋亡水平显着，但突变腭架中的细胞增殖未改变。在分子水平上，我们发现 Fgf10 在发育中的上颚中相对于 Jagged2 和 Tgfbeta3 具有上位性。值得注意的是，在 Fgf10 突变体中，Jagged2 的表达在整个腭上皮中下调，而 Tgfbeta3 在口腔侧的腭上皮中错误表达。我们的结果表明，间充质表达的 Fgf10 对于 MEE 细胞的存活以及哺乳动物腭发育过程中腭上皮中 Jagged2 和 Tgfbeta3 的正常表达是必需的。 (C) 2004 Elsevier Inc. 保留所有权利。
Mammalian palatogenesis depends on interactions between the stomodium-derived epithelium and the cranial neural crest-derived ectomesenchyme. Fibroblast growth factor 10 (FGF10) is a mesenchymal signaling factor that guides the morphogenesis of multiple organs through tissue-tissue interactions. This is consistent with widespread agenesis and dysgenesis of organs observed in Fgf10(-/-) mice. In this study, we report the presence of a wide-open cleft secondary palate in Fgf10 homozygous null mutant mice. Fgf10 transcripts were detected in the palatal mesenchyme from E 11.5 to E 13.5 during normal palatogenesis and were enriched in the anterior and middle portions of the palatal shelves. In Fgf10(-/-) embryos, histological analyses revealed aberrant adhesion of the palatal shelves with the tongue in the anterior and fusion with the mandible in the middle and posterior beginning at E13.5, which could prevent normal elevation of the palatal shelves leading to a cleft palate. TUNEL and BrdU assays demonstrated significant levels of apoptosis in the medial edge epithelium (MEE) but unaltered cell proliferation in mutant palatal shelves. At the molecular level, we show that Fgf10 is epistatic to Jagged2 and Tgfbeta3 in the developing palate. Notably, the expression of Jagged2 is downregulated throughout the palate epithelium in Fgf10 mutants while Tgfbeta3 is misexpressed in the palatal epithelium at the oral side. Our results demonstrate that mesenchymally expressed Fgf10 is necessary for the survival of MEE cells and for the normal expression of Jagged2 and Tgfbeta3 in the palatal epithelium during mammalian palatogenesis. (C) 2004 Elsevier Inc. All rights reserved.