Sullivan-Brown Jessica, Schottenfeld Jodi, Okabe Noriko, Hostetter Christine L, Serluca Fabrizio C, Thiberge Stephan Y, Burdine Rebecca D
Department of Molecular Biology, Princeton University, Washington Road, Mof 433, Princeton, NJ 08544, USA.
Dev Biol. 2008 Feb 15;314(2):261-75. doi: 10.1016/j.ydbio.2007.11.025. Epub 2007 Dec 3.
Zebrafish are an attractive model for studying the earliest cellular defects occurring during renal cyst formation because its kidney (the pronephros) is simple and genes that cause cystic kidney diseases (CKD) in humans, cause pronephric dilations in zebrafish. By comparing phenotypes in three different mutants, locke, swt and kurly, we find that dilations occur prior to 48 hpf in the medial tubules, a location similar to where cysts form in some mammalian diseases. We demonstrate that the first observable phenotypes associated with dilation include cilia motility and luminal remodeling defects. Importantly, we show that some phenotypes common to human CKD, such as an increased number of cells, are secondary consequences of dilation. Despite having differences in cilia motility, locke, swt and kurly share similar cystic phenotypes, suggesting that they function in a common pathway. To begin to understand the molecular mechanisms involved in cyst formation, we have cloned the swt mutation and find that it encodes a novel leucine rich repeat containing protein (LRRC50), which is thought to function in correct dynein assembly in cilia. Finally, we show that knock-down of polycystic kidney disease 2 (pkd2) specifically causes glomerular cysts and does not affect cilia motility, suggesting multiple mechanisms exist for cyst formation.
斑马鱼是研究肾囊肿形成过程中最早出现的细胞缺陷的理想模型，因为其肾脏（前肾）结构简单，而且在人类中导致多囊肾病（CKD）的基因，在斑马鱼中会导致前肾扩张。通过比较三种不同突变体locke、swt和kurly的表型，我们发现内侧肾小管在48 hpf之前就出现了扩张，这一位置与某些哺乳动物疾病中囊肿形成的位置相似。我们证明，与扩张相关的第一个可观察到的表型包括纤毛运动和管腔重塑缺陷。重要的是，我们表明人类CKD常见的一些表型，如细胞数量增加，是扩张的继发后果。尽管locke、swt和kurly在纤毛运动方面存在差异，但它们具有相似的囊性表型，这表明它们在共同的途径中发挥作用。为了开始了解囊肿形成所涉及的分子机制，我们克隆了swt突变，发现它编码一种含有新型富含亮氨酸重复序列的蛋白质（LRRC50），该蛋白质被认为在纤毛中正确组装动力蛋白中发挥作用。最后，我们表明敲低多囊肾病2（pkd2）会特异性地导致肾小球囊肿，并且不影响纤毛运动，这表明囊肿形成存在多种机制。
