Dkk1 and Dkk2 regulate epicardial specification during mouse heart development.
Dkk1 and Dkk2 regulate epicardial specification during mouse heart development.
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DOI：
10.1016/j.ijcard.2010.04.007
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发表时间：
2011-07-15
影响因子：
3.5
通讯作者：
Westphal H
中科院分区：
文献类型：
--
作者：
Phillips MD;Mukhopadhyay M;Poscablo C;Westphal H
Dkk1和Dkk2与LRP5和LRP6相互作用，在发育过程中调节典型的Wnt信号，并在发育中的心脏中表达。然而，任何一种基因的功能缺失突变本身都不会产生可识别的心脏表型。采用标准的饲养技术，将Dkk1缺失和Dkk2缺失的小鼠系杂交产生双缺失胚胎，并用组织学和免疫组织化学方法对其进行检测。双空胚在围产期死亡，其大体头型与Dkk1空胚相似。在检查晚期心脏时，我们观察到心肌缺损包括室间隔缺损。在早期阶段，双突变心脏表现为心肌和心外膜增生。心肌肥大与细胞增殖的适度增加有关，但心外膜细胞增多与此无关。相反，靠近肝脏的心外膜前体细胞区显示心脏特异性间隙连接蛋白Connexin 43的表达范围扩大。Dkk1和Dkk2都抑制Wnt信号，调节早期心肌增殖，并且各自可以弥补对方在该作用中的损失。Wnt信号在早期阶段调节两个心脏区的心肌增殖。此外，通过连接蛋白43的表达测量，Wnt信号足以增加心外膜前规格，导致心外膜细胞过多，并可能导致后来的缺陷。
Dkk1 and Dkk2 interact with LRP5 and LRP6 to modulate canonical Wnt signaling during development, and are known to be expressed in the developing heart. However, a loss-of-function mutation in either gene by itself produces no discernable heart phenotype. Using standard husbandry techniques, Dkk1 null and Dkk2 null mouse lines were crossed to create double null embryos, which we examined using histological and immunohistochemical methods. Double null embryos die perinatally, with a gross head phenotype reminiscent of Dkk1 null embryos. Upon examination of late stage hearts, we observe myocardial defects including ventricular septal defects. At earlier stages, double mutant hearts show myocardial and epicardial hyperplasia. Myocardial hypertrophy is associated with a moderate increase in cell proliferation, but epicardial hypercellularity is not. Rather, the field of proepicardial precursor cells near the liver shows a broadening of expression for the cardiac-specific gap junction protein Connexin 43. Dkk1 and Dkk2 both inhibit Wnt signaling to regulate early myocardial proliferation and each can compensate for the loss of the other in that role. Wnt signaling regulates myocardial proliferation in both heart fields at early stages. Additionally, Wnt signaling is sufficient to increase proepicardial specification as measured by Connexin 43 expression, resulting in a hypercellular epicardium and perhaps contributing to later defects.
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DOI：
10.1073/pnas.0704044104
发表时间：
2007-06-26
影响因子：
11.1
作者：
Kwon, Chulan;Arnold, Joshua;Srivastava, Deepak
通讯作者：
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影响因子：
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2.6
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Niehrs, C
影响因子：
7.8
作者：
Liebner, S;Cattelino, A;Dejana, E
通讯作者：
Dejana, E
影响因子：
2.6
作者：
Saffitz, Jeffrey E.;Asimaki, Angeliki;Huang, Hayden
通讯作者：
Huang, Hayden