The ion channel polycystin-2 is required for left-right axis determination in mice
The ion channel polycystin-2 is required for left-right axis determination in mice
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DOI：
10.1016/s0960-9822(02)00869-2
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发表时间：
2002-06-04
期刊：
影响因子：
9.2
通讯作者：
Dworniczak, B
中科院分区：
文献类型：
--
作者：
Pennekamp, P;Karcher, C;Dworniczak, B
偏侧性的产生取决于涉及不对称表达基因nodal、Ebaf、Leftb和Pitx 2的途径[1-3]。在小鼠中，淋巴结级联的上游需要淋巴结单纤毛[4]。在鸡和青蛙中，间隙连接在节点/组织者形成之前是必不可少的[5，6]。假设离子通道的差异活性引起通过间隙连接的单向转移，导致不对称基因表达[3，6]。PKD 2，如果突变会导致人类常染色体显性多囊肾病（ADPKD），编码钙释放通道多囊蛋白-2 [7-11]。我们已经在小鼠中产生了Pkd 2的敲除等位基因。除了先前描述的畸形外[12]，纯合突变胚胎显示右肺异构、胚胎转向随机化、心脏成环和腹部位置。左侧板中胚层（LPM）不表达Leftb和nodal，底板不表达Ebaf。Pitx 2在LPM后部双侧表达，但前部缺失。PKD 2在头褶和早期体节阶段普遍表达，在底板和脊索中表达水平较高。然而，胚胎中线，和正常水平的Foxa 2和shh的表达，表明多囊蛋白-2作用下游或平行于shh和上游的节点级联。
Generation of laterality depends on a pathway which involves the asymmetrically expressed genes nodal, Ebaf, Leftb, and Pitx2 [1-3]. In mouse, node monocilia are required upstream of the nodal cascade [4]. In chick and frog, gap junctions are essential prior to node/organizer formation [5, 6]. It was hypothesized that differential activity of ion channels gives rise to unidirectional transfer through gap junctions, resulting in asymmetric gene expression [3, 6]. PKD2, which if mutated causes autosomal dominant polycystic kidney disease (ADPKD) in humans, encodes the calcium release channel polycystin-2 [7-11]. We have generated a knockout allele of Pkd2 in mouse. In addition to malformations described previously [12], homozygous mutant embryos showed right pulmonary isomerism, randomization of embryonic turning, heart looping, and abdominal situs. Leftb and nodal were not expressed in the left lateral plate mesoderm (LPM), and Ebaf was absent from floorplate. Pitx2 was bilaterally expressed in posterior LPM but absent anteriorly. Pkd2 was ubiquitously expressed at headfold and early somite stages, with higher levels in floorplate and notochord. The embryonic midline, however, was present, and normal levels of Foxa2 and shh were expressed, suggesting that polycystin-2 acts downstream or in parallel to shh and upstream of the nodal cascade.