Cardiovascular, skeletal, and renal defects in mice with a targeted disruption of the Pkd1 gene
Cardiovascular, skeletal, and renal defects in mice with a targeted disruption of the Pkd1 gene
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DOI：
10.1073/pnas.211191098
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发表时间：
2001-10-09
影响因子：
11.1
通讯作者：
Sandford, R
中科院分区：
文献类型：
--
作者：
Boulter, C;Mulroy, S;Sandford, R
常染色体显性多囊肾病（ADPKD）以肾脏、肝脏和胰腺的囊肿形成为特征，常伴有心血管异常，如高血压、二尖瓣脱垂和颅内动脉瘤。它是由编码多囊蛋白-1和-2的PKD1或PKD2突变引起的，它们共同形成细胞表面非选择性阳离子离子通道。Pkd2-/-小鼠在肾脏和胰腺中有囊肿和心隔缺陷，而Pkd1(del34) -/-和Pkd1(L) -/-小鼠有囊肿但没有心脏异常，尽管后者报道了血管脆性。在这里，我们描述了携带Pkd1（Pkd1(del17-21 beta geo)）靶向突变的小鼠，该突变通过使用lacZ报告基因来定义其表达模式，并可能确定多囊蛋白-1的新功能。虽然Pkd1(del17-21 β geo) +/-成年小鼠会出现肾和肝囊肿，但Pkd1(del17-21 β geo) +/-胚胎在胚胎期13.5-14.5天死于原发性心血管缺陷，包括双流出右心室、心肌紊乱和房室分隔异常。骨骼发育也严重受损。这些异常与Pkd1表达的主要位点相关。在肾形成过程中，Pkd1在胚胎15.5天成熟的小管上皮细胞中表达。这种表达与Pkd1(del34) -/-、Pkd1(L) -/-和Pkd(2) -/-小鼠中囊肿形成的开始一致，支持了多囊蛋白-1和多囊蛋白-2在体内相互作用的假设，它们不能相互作用导致小管形态和功能异常。
Autosomal dominant polycystic kidney disease (ADPKD) is characterized by cyst formation in the kidney, liver, and pancreas and is associated often with cardiovascular abnormalities such as hypertension, mitral valve prolapse, and intracranial aneurysms. It is caused by mutations in PKD1 or PKD2, encoding polycystin-1 and -2, which together form a cell surface nonselective cation ion channel. Pkd2-/- mice have cysts in the kidney and pancreas and defects in cardiac septation, whereas Pkd1(del34) -/- and Pkd1(L) -/- mice have cysts but no cardiac abnormalities, although vascular fragility was reported in the latter. Here we describe mice carrying a targeted mutation in Pkd1 (Pkd1(del17-21 beta geo)), which defines its expression pattern by using a lacZ reporter gene and may identify novel functions for polycystin-1. Although Pkd1(del17-21 beta geo) +/- adult mice develop renal and hepatic cysts, Pkd1(del17-21 beta geo) +/- embryos die at embryonic days 13.5-14.5 from a primary cardiovascular defect that includes double outflow right ventricle, disorganized myocardium, and abnormal atrio-ventricular septation. Skeletal development is also severely compromised. These abnormalities correlate with the major sites of Pkd1 expression. During nephrogenesis, Pkd1 is expressed in maturing tubular epithelial cells from embryonic day 15.5. This expression coincides with the onset of cyst formation in Pkd1(del34) -/-, Pkd1(L) -/-, and Pkd(2) -/- mice, supporting the hypothesis that polycystin-1 and polycystin-2 interact in vivo and that their failure to do so leads to abnormalities in tubule morphology and function.