用斑马鱼模拟人类下尿路畸形。

IF 2.4 Q1 PEDIATRICS
Caroline M Kolvenbach, Gabriel C Dworschak, Johanna M Rieke, Adrian S Woolf, Heiko Reutter, Benjamin Odermatt, Alina C Hilger
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引用次数: 0

摘要

分子生物学的进步使我们对人类先天性下尿路(即膀胱和尿道)畸形的遗传原因有了更深入的了解。最近,我们首次发现了导致孤立性下尿路解剖性梗阻(LUTO)的 BNC2 基因中的致病变体,并发现了 WNT3 和 SLC20A1 基因与膀胱萎缩-尿道外翻综合征(BEEC)的发病机制有关。要从人类基因数据中推断出候选基因,需要有证据证明它们对下尿路发育的影响,并证明所发现的基因变异具有致病性。斑马鱼(Danio rerio)作为下尿路的脊椎动物模型有很多优点。斑马鱼繁殖速度快,后代数量多,肾脏和下尿路解剖结构相似,而且易于通过基于 Morpholino® 的基因敲除或 CRISPR/Cas 编辑进行遗传操作,这些都是它的优势。此外,利用全贴片原位杂交(WISH)对参与尿路发育的知名分子进行标记染色,以及使用在组织特异性启动子下表达荧光蛋白的转基因品系,可以方便地观察转基因斑马鱼的表型异常。检查排泄器官功能的试验也可以用斑马鱼在体内模拟。在斑马鱼身上使用这些多种技术的方法不仅能快速有效地研究从人类数据中得出的下尿路畸形候选基因,还能谨慎地将非哺乳类脊椎动物的因果关系转移到人类身上。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Modelling human lower urinary tract malformations in zebrafish.

Modelling human lower urinary tract malformations in zebrafish.

Modelling human lower urinary tract malformations in zebrafish.

Advances in molecular biology are improving our understanding of the genetic causes underlying human congenital lower urinary tract (i.e., bladder and urethral) malformations. This has recently led to the identification of the first disease-causing variants in the gene BNC2 for isolated lower urinary tract anatomical obstruction (LUTO), and of WNT3 and SLC20A1 as genes implicated in the pathogenesis of the group of conditions called bladder-exstrophy-epispadias complex (BEEC). Implicating candidate genes from human genetic data requires evidence of their influence on lower urinary tract development and evidence of the found genetic variants' pathogenicity. The zebrafish (Danio rerio) has many advantages for use as a vertebrate model organism for the lower urinary tract. Rapid reproduction with numerous offspring, comparable anatomical kidney and lower urinary tract homology, and easy genetic manipulability by Morpholino®-based knockdown or CRISPR/Cas editing are among its advantages. In addition, established marker staining for well-known molecules involved in urinary tract development using whole-mount in situ hybridization (WISH) and the usage of transgenic lines expressing fluorescent protein under a tissue-specific promoter allow easy visualization of phenotypic abnormalities of genetically modified zebrafish. Assays to examine the functionality of the excretory organs can also be modeled in vivo with the zebrafish. The approach of using these multiple techniques in zebrafish not only enables rapid and efficient investigation of candidate genes for lower urinary tract malformations derived from human data, but also cautiously allows transferability of causality from a non-mammalian vertebrate to humans.

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