Cse1l is a negative regulator of CFTR-dependent fluid secretion.
Cse1l is a negative regulator of CFTR-dependent fluid secretion.
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DOI：
10.1016/j.cub.2010.09.012
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发表时间：
2010-10-26
期刊：
影响因子：
9.2
通讯作者：
Stainier, Didier Y. R.
中科院分区：
文献类型：
--
作者：
Bagnat, Michel;Navis, Adam;Herbstreith, Sara;Brand-Arzamendi, Koroboshka;Curado, Silvia;Gabriel, Sherif;Mostov, Keith;Huisken, Jan;Stainier, Didier Y. R.
通过囊性纤维化跨膜电导调节器（CFTR）通道的氯离子转运是调节脊椎动物体液分泌的关键步骤。CFTR功能的丧失导致囊性纤维化（CF），这是一种影响肺、胰腺、肝脏、肠和输精管的疾病。相反，通道的不受控制的激活导致液体分泌增加，并在包括霍乱和其他分泌性肾炎以及多囊肾病（PKD）在内的几种疾病和病症中起主要作用。由于缺乏遗传模型，理解CFTR活性如何在体内调节受到限制。在这里，我们在斑马鱼中使用了正向遗传方法来发现CFTR调节子。我们报告的识别，分离和表征的突变斑马鱼cse1l基因，导致肠道管的突然和戏剧性的扩张。我们表明，这种表型是由于CFTR通道的不受控制的激活引起的液体快速积累的结果。在斑马鱼胚胎和哺乳动物细胞中的分析表明，Cse1l是CFTR依赖性液体分泌的负调节剂。这项工作证明了流体稳态在发育中的重要性，并建立了斑马鱼作为一个急需的模型系统，研究CFTR的调控在体内。
Transport of chloride through the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) channel is a key step in regulating fluid secretion in vertebrates. Loss of CFTR function leads to cystic fibrosis (CF), a disease that affects the lungs, pancreas, liver, intestine and vas deferens. Conversely, un-controlled activation of the channel leads to increased fluid secretion and plays a major role in several diseases and conditions including cholera and other secretory diarrheas as well as Polycystic Kidney Disease (PKD). Understanding how CFTR activity is regulated in vivo has been limited by the lack of a genetic model. Here, we used a forward genetic approach in zebrafish to uncover CFTR regulators. We report the identification, isolation and characterization of a mutation in the zebrafish cse1l gene that leads to the sudden and dramatic expansion of the gut tube. We show that this phenotype results from a rapid accumulation of fluid due to the un-controlled activation of the CFTR channel. Analyses in zebrafish embryos and mammalian cells indicate that Cse1l is a negative regulator of CFTR-dependent fluid secretion. This work demonstrates the importance of fluid homeostasis in development and establishes the zebrafish as a much needed model system to study CFTR regulation in vivo.
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