Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland.
Institute of Anatomy, University of Zurich, Zurich, Switzerland.
Sci Rep. 2019 Mar 18;9(1):4750. doi: 10.1038/s41598-019-41202-4.
Although structural nuclear pore proteins (nucleoporins) are seemingly required in every cell type to assemble a functional nuclear transport machinery, mutations or deregulation of a subset of them have been associated with specific human hereditary diseases. In particular, previous genetic studies of patients with nephrotic syndrome identified mutations in Nup107 that impaired the expression or the localization of its direct partner at nuclear pores, Nup133. In the present study, we characterized the zebrafish nup133 orthologous gene and its expression pattern during larval development. Using a morpholino-mediated gene knockdown, we show that partial depletion of Nup133 in zebrafish larvae leads to the formation of kidney cysts, a phenotype that can be rescued by co-injection of wild type mRNA. Analysis of different markers for tubular and glomerular development shows that the overall kidney development is not affected by nup133 knockdown. Likewise, no gross defect in nuclear pore complex assembly was observed in these nup133 morphants. On the other hand, nup133 downregulation results in proteinuria and moderate foot process effacement, mimicking some of the abnormalities typically featured by patients with nephrotic syndrome. These data indicate that nup133 is a new gene required for proper glomerular structure and function in zebrafish.
虽然结构核孔蛋白（核孔蛋白）在每种细胞类型中似乎都需要组装一个功能性的核转运机制，但它们中的一部分突变或失调与特定的人类遗传性疾病有关。特别是，以前对肾病综合征患者的遗传研究发现，Nup107 的突变会损害其在核孔处的直接伴侣 Nup133 的表达或定位。在本研究中，我们对斑马鱼 nup133 直系同源基因及其在幼虫发育过程中的表达模式进行了表征。使用一种基于 morpholino 的基因敲低方法，我们表明在斑马鱼幼虫中部分耗尽 Nup133 会导致肾脏囊肿的形成，这种表型可以通过共注射野生型 mRNA 得到挽救。对不同的管状和肾小球发育标记物的分析表明，nup133 敲低对整体肾脏发育没有影响。同样，在这些 nup133 形态发生体中也没有观察到核孔复合物组装的明显缺陷。另一方面，nup133 的下调导致蛋白尿和中度足突消失，模拟了肾病综合征患者的一些异常特征。这些数据表明，nup133 是斑马鱼中肾小球结构和功能所必需的一个新基因。
