Cse1l is a negative regulator of CFTR-dependent fluid secretion.

Journal Article

Transport of chloride through the cystic fibrosis transmembrane conductance regulator (CFTR) channel is a key step in regulating fluid secretion in vertebrates [1, 2]. Loss of CFTR function leads to cystic fibrosis [1, 3, 4], a disease that affects the lungs, pancreas, liver, intestine, and vas deferens. Conversely, uncontrolled activation of the channel leads to increased fluid secretion and plays a major role in several diseases and conditions including cholera [5, 6] and other secretory diarrheas [7] as well as polycystic kidney disease [8-10]. 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 uncontrolled activation of the CFTR channel. Analyses in zebrafish larvae 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.

Full Text

Duke Authors

Cited Authors

  • Bagnat, M; Navis, A; Herbstreith, S; Brand-Arzamendi, K; Curado, S; Gabriel, S; Mostov, K; Huisken, J; Stainier, DYR

Published Date

  • October 26, 2010

Published In

Volume / Issue

  • 20 / 20

Start / End Page

  • 1840 - 1845

PubMed ID

  • 20933420

Electronic International Standard Serial Number (EISSN)

  • 1879-0445

Digital Object Identifier (DOI)

  • 10.1016/j.cub.2010.09.012

Language

  • eng

Conference Location

  • England