Pkd1 and Pkd2 Are Required for Normal Placental Development
Pkd1 and Pkd2 Are Required for Normal Placental Development
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DOI：
10.1371/journal.pone.0012821
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发表时间：
2010-09-16
期刊：
影响因子：
3.7
通讯作者：
Watnick, Terry
中科院分区：
文献类型：
--
作者：
Garcia-Gonzalez, Miguel A.;Outeda, Patricia;Watnick, Terry
背景：常染色体显性多囊肾病 (ADPKD) 是遗传性肾衰竭的常见原因，由 PKD1 和 PKD2 突变引起。该疾病的特征是局灶性囊肿形成，涉及大部分囊肿中野生型等位基因的体细胞突变。与二次打击机制一致，Pkd1 或 Pkd2 失活突变的纯合子小鼠会出现囊性肾、水肿和出血，并且通常在妊娠中期死亡。囊性肾病不太可能是胎儿流产的原因，因为完成妊娠不需要肾功能。一种假设是胚胎死亡是由于血管渗漏或心脏病引起的。方法/主要发现：在这些研究中，我们使用了一系列转基因 Pkd1 和 Pkd2 小鼠模型来研究突变胚胎中胚胎致死的原因。由于胎盘缺陷是胎儿流产的常见原因，我们对 Pkd1 缺失小鼠的胎盘进行了组织病理学分析，并检测到从 E12.5 开始的迷路层异常。我们使用四倍体聚集和 Meox2 Cre 重组酶条件性灭活 Pkd1 进行胎盘挽救实验。我们发现这两种策略都提高了 Pkd1 无效胚胎的活力。内皮细胞中 Pkd1 和 Pkd2 的选择性失活导致羊水过多和异常，类似于 Pkd1(-/-) 胎盘中观察到的情况。然而，内皮细胞特异性删除 Pkd1 或 Pkd2 并没有产生在无效动物中观察到的显着血管表型。结论/意义：胎盘异常导致 Pkd(-/-) 胚胎的胎儿死亡。 Pkd1 或 Pkd2 的内皮细胞特异性缺失概括了在 Pkd 缺失动物中观察到的一部分发现。我们的研究揭示了多囊蛋白在维持血管完整性方面的复杂作用。
Background: Autosomal dominant polycystic kidney disease (ADPKD) is a common cause of inherited renal failure that results from mutations in PKD1 and PKD2. The disorder is characterized by focal cyst formation that involves somatic mutation of the wild type allele in a large fraction of cysts. Consistent with a two-hit mechanism, mice that are homozygous for inactivating mutations of either Pkd1 or Pkd2 develop cystic kidneys, edema and hemorrhage and typically die in midgestation. Cystic kidney disease is unlikely to be the cause of fetal loss since renal function is not required to complete gestation. One hypothesis is that embryonic demise is due to leaky vessels or cardiac pathology.Methodology/Principal Findings: In these studies we used a series of genetically modified Pkd1 and Pkd2 murine models to investigate the cause of embryonic lethality in mutant embryos. Since placental defects are a frequent cause of fetal loss, we conducted histopathologic analyses of placentas from Pkd1 null mice and detected abnormalities of the labyrinth layer beginning at E12.5. We performed placental rescue experiments using tetraploid aggregation and conditional inactivation of Pkd1 with the Meox2 Cre recombinase. We found that both strategies improved the viability of Pkd1 null embryos. Selective inactivation of Pkd1 and Pkd2 in endothelial cells resulted in polyhydramnios and abnormalities similar to those observed in Pkd1(-/-) placentas. However, endothelial cell specific deletion of Pkd1 or Pkd2 did not yield the dramatic vascular phenotypes observed in null animals.Conclusions/Significance: Placental abnormalities contribute to the fetal demise of Pkd(-/-) embryos. Endothelial cell specific deletion of Pkd1 or Pkd2 recapitulates a subset of findings seen in Pkd null animals. Our studies reveal a complex role for polycystins in maintaining vascular integrity.