Placental but not heart defects are associated with elevated hypoxia-inducible factor α levels in mice lacking prolyl hydroxylase domain protein 2
Placental but not heart defects are associated with elevated hypoxia-inducible factor α levels in mice lacking prolyl hydroxylase domain protein 2
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DOI：
10.1128/mcb.00425-06
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发表时间：
2006-11-01
影响因子：
5.3
通讯作者：
Fong, Guo-Hua
中科院分区：
文献类型：
--
作者：
Takeda, Kotaro;Ho, Vivienne C.;Fong, Guo-Hua
PHD 1、PHD 2和PHD 3是脯氨酰羟化酶结构域蛋白，其调节低氧诱导因子α亚基（HIF-α）的稳定性。为了确定单个PHD在小鼠发育过程中的作用，我们破坏了所有三个Phd基因，发现Phd 2（-/-）胚胎在胚胎第12.5和14.5天之间死亡，而Phd 1（-/-）或Phd 3（-/-）小鼠显然正常。在Phd 2（-/-）小鼠中，胚胎死亡之前存在严重的胎盘和心脏缺陷。胎盘缺陷包括胎盘分支形态发生显著减少，海绵滋养细胞广泛穿透迷路，滋养层巨细胞分布异常。几种滋养层标志物的表达也发生了改变，包括海绵滋养层标志物Mash 2的增加和谷胱甘肽标志物Tfeb和Gem的减少。在心脏中，小梁发育不良，心肌明显变薄，室间隔形成不完全。令人惊讶的是，虽然胎盘和胚胎中的HIF-α蛋白水平有显著的整体增加，但心脏中没有特异性的HIF-α增加。总之，这些数据表明，在所有三种PHD蛋白中，PHD 2是小鼠胚胎发生过程中唯一必需的。
PHD1, PHD2, and PHD3 are prolyl hydroxylase domain proteins that regulate the stability of hypoxia-inducible factor alpha subunits (HIF-alpha). To determine the roles of individual PHDs during mouse development, we disrupted all three Phd genes and found that Phd2(-/-) embryos died between embryonic days 12.5 and 14.5 whereas Phd1(-/-) or Phd3(-/-) mice were apparently normal. In Phd2(-/-) mice, severe placental and heart defects preceded embryonic death. Placental defects included significantly reduced labyrinthine branching morphogenesis, widespread penetration of the labyrinth by spongiotrophoblasts, and abnormal distribution of trophoblast giant cells. The expression of several trophoblast markers was also altered, including an increase in the spongiotrophoblast marker Mash2 and decreases in the labyrinthine markers Tfeb and Gem]. In the heart, trabeculae were poorly developed, the myocardium was remarkably thinner, and interventricular septum was incompletely formed. Surprisingly, while there were significant global increases in HIF-alpha protein levels in the placenta and the embryo proper, there was no specific HIF-alpha increase in the heart. Taken together, these data indicate that among all three PHD proteins, PHD2 is uniquely essential during mouse embryogenesis.