Over-expression of Fgf8 in cardiac neural crest cells leads to persistent truncus arteriosus
Over-expression of Fgf8 in cardiac neural crest cells leads to persistent truncus arteriosus
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心脏神经嵴细胞中 Fgf8 的过度表达导致持续性动脉干
DOI：
10.1007/s10735-021-09956-2
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发表时间：
2021-02
影响因子：
3.2
通讯作者：
Liu Chao
中科院分区：
文献类型：
--
作者：
Tian Aijuan;Wang Shangqi;Wang Haoru;Li Nan;Liu Han;Zhou Hailing;Chen Xiaoyan;Liu Xuena;Deng Jiamin;Xiao Jing;Liu Chao
在心脏发生过程中，流出道经历了复杂的形态发生，包括大血管的重新排列以及主动脉和肺动脉干的分离。FGF 8在流出道形态发生中的缺乏已经得到了很好的研究，然而，过量的FGF 8对流出道发育的影响仍然未知。在本研究中，Rosa 26 R-Fgf 8基因敲入的等位基因被Wnt 1-cre转基因在小鼠神经嵴细胞中组成性激活，推测神经嵴细胞是流出道的内膜垫。令人惊讶的是，Wnt 1-cre; Rosa 26 R-Fgf 8小鼠胚胎表现出持续的动脉干，并在E15.5之前死亡。Wnt 1-cre; Rosa 26 R-Fgf 8动脉干中的心脏神经嵴细胞没有像WT对照中那样退化，而是增殖成增厚的内膜垫，然后阻断从心腔到肺的血液流出，这导致胚胎死亡。虽然螺旋动脉间隔未能形成，但Wnt 1-cre; Rosa 26 R-Fgf 8动脉干内皮细胞和平滑肌细胞的分化受到的影响不大。谱系示踪显示神经嵴来源的细胞聚集在垫层，但不能分化为Wnt 1-cre; Rosa 26 R-Fgf 8动脉干内皮细胞。进一步的研究显示，在Wnt 1-cre; Rosa 26 R-Fgf 8动脉干内皮细胞中，p-Akt和p-Erk免疫染色减少，Bmp 2和Bmp 4转录减少。提示Fgf 8在心脏神经嵴的过度表达可能通过抑制内皮细胞分化和刺激内膜垫细胞增殖而影响动脉间隔的形成，提示永存动脉干可能是一种新的病因。
During cardiogenesis, the outflow tract undergoes a complicated morphogenesis, including the re-alignment of the great blood vessels, and the separation of aorta and pulmonary trunk. The deficiency of FGF8 in the morphogenesis of outflow tract has been well studied, however, the effect of over-dosed FGF8 on the development of outflow tract remains unknown. In this study, Rosa26R-Fgf8 knock-in allele was constitutively activated by Wnt1-cre transgene in the mouse neural crest cells presumptive for the endocardial cushion of outflow tract. Surprisingly, Wnt1-cre; Rosa26R-Fgf8 mouse embryos exhibited persistent truncus arteriosus and died prior to E15.5. The cardiac neural crest cells in Wnt1-cre; Rosa26R-Fgf8 truncus arteriosus did not degenerate as in WT controls, but proliferated into a thickened endocardial cushion and then, blocked the blood outflow from cardiac chambers into the lungs, which resulted in the embryonic lethality. Although the spiral aorticopulmonary septum failed to form, the differentiaion of the endothelium and smooth muscle in the Wnt1-cre; Rosa26R-Fgf8 truncus arteriosus were impacted little. However, lineage tracing assay showed that the neural crest derived cells aggregated in the cushion layer, but failed to differentiate into the endothelium of Wnt1-cre; Rosa26R-Fgf8 truncus arteriosus. Further investigation displayed the reduced p-Akt and p-Erk immunostaining, and the decreased Bmp2 and Bmp4 transcription in the endothelium of Wnt1-cre; Rosa26R-Fgf8 truncus arteriosus. Our findings suggested that Fgf8 over-expression in cardiac neural crest impaired the formation of aorticopulmonary septum by suppressing the endothelial differentiation and stimulating the proliferation of endocardial cushion cells, which implicated a novel etiology of persistent truncus arteriosus.
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DOI：
10.1353/mis.1991.0053
发表时间：
2011-10
期刊：
The Missouri Review
影响因子：
--
作者：
S. Gaines
通讯作者：
S. Gaines
影响因子：
7.2
作者：
Dye, Bailey;Lincoln, Joy
通讯作者：
Lincoln, Joy
影响因子：
4.6
作者：
Jun Li;Kenneth C. Liu;F. Jin;M. Lu;Jonathan A. Epstein
通讯作者：
Jun Li;Kenneth C. Liu;F. Jin;M. Lu;Jonathan A. Epstein
影响因子：
4.6
作者：
Masahide Sakabe;H. Kokubo;Y. Nakajima;Y. Saga
通讯作者：
Masahide Sakabe;H. Kokubo;Y. Nakajima;Y. Saga
影响因子：
7.2
作者：
Yamagishi, Hiroyuki
通讯作者：
Yamagishi, Hiroyuki