ZFIN ID: ZDB-PUB-101018-11
Cse1l Is a Negative Regulator of CFTR-Dependent Fluid Secretion
Bagnat, M., Navis, A., Herbstreith, S., Brand-Arzamendi, K., Curado, S., Gabriel, S., Mostov, K., Huisken, J., and Stainier, D.Y.
Date: 2010
Source: Current biology : CB   20(20): 1840-1845 (Journal)
Registered Authors: Bagnat, Michel, Curado, Silvia, Huisken, Jan, Stainier, Didier
Keywords: none
MeSH Terms:
  • Animals
  • Body Fluids
  • Cell Line
  • Cellular Apoptosis Susceptibility Protein/metabolism*
  • Cystic Fibrosis Transmembrane Conductance Regulator/metabolism*
  • Dogs
  • Gastrointestinal Tract/abnormalities
  • Gastrointestinal Tract/embryology
  • Gastrointestinal Tract/metabolism*
  • Genes, Recessive
  • Green Fluorescent Proteins
  • Homeostasis/physiology*
  • Immunoprecipitation
  • Microscopy, Confocal
  • Mutation/genetics
  • Zebrafish
PubMed: 20933420 Full text @ Curr. Biol.
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.