Redundant and dosage sensitive requirements for Fgf3 and Fgf10 in cardiovascular development.
Redundant and dosage sensitive requirements for Fgf3 and Fgf10 in cardiovascular development.
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DOI：
10.1016/j.ydbio.2011.05.671
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发表时间：
2011-08-15
影响因子：
2.7
通讯作者：
Mansour SL
中科院分区：
文献类型：
--
作者：
Urness LD;Bleyl SB;Wright TJ;Moon AM;Mansour SL
心脏发育需要多个细胞群的贡献和协调信号相互作用，包括内脏和咽中胚层、后神经嵴和心外膜。在这里，我们报道 Fgf3 和 Fgf10 在这些心血管祖细胞内和附近动态表达，在早期小鼠心血管发育的多个方面具有冗余和剂量敏感的需求。具有 Fgf3−/+;Fgf10−/−、Fgf3−/−;Fgf10−/+ 和 Fgf3−/−;Fgf10−/− 基因型的胚胎形成了一系列对胚胎存活率越来越严重的等位基因，双突变体在 E11.5 时死亡。对 E11.5-E13.5 三个突变等位基因和 E9.5-E11.0 双突变体的胚胎进行形态学分析，结果显示存在多种心血管缺陷，影响流出道、心室间隔、房室垫、心室心肌、背侧间质突出、肺动脉、心外膜和第四咽弓动脉。对 E8.0-E10.5 双突变体中分子标记的评估揭示了每个祖细胞群体的异常，并表明 Fgf3 和 Fgf10 不是心血管祖细胞规范所必需的，而是它们正常发育协调所必需的。这些结果意味着 FGF3 或 FGF10 的编码或调节突变可能导致人类先天性心脏缺陷。
Heart development requires contributions from, and coordinated signaling interactions between, several cell populations, including splanchnic and pharyngeal mesoderm, postotic neural crest and the proepicardium. Here we report that Fgf3 and Fgf10, which are expressed dynamically in and near these cardiovascular progenitors, have redundant and dosage sensitive requirements in multiple aspects of early murine cardiovascular development. Embryos with Fgf3−/+;Fgf10−/−, Fgf3−/−;Fgf10−/+ and Fgf3−/−;Fgf10−/− genotypes formed an allelic series of increasing severity with respect to embryonic survival, with double mutants dead by E11.5. Morphologic analysis of embryos with three mutant alleles at E11.5–E13.5 and double mutants at E9.5–E11.0 revealed multiple cardiovascular defects affecting the outflow tract, ventricular septum, atrioventricular cushions, ventricular myocardium, dorsal mesenchymal protrusion, pulmonary arteries, epicardium and fourth pharyngeal arch artery. Assessment of molecular markers in E8.0–E10.5 double mutants revealed abnormalities in each progenitor population, and suggest that Fgf3 and Fgf10 are not required for specification of cardiovascular progenitors, but rather for their normal developmental coordination. These results imply that coding or regulatory mutations in FGF3 or FGF10 could contribute to human congenital heart defects.
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