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

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.

Pubmed ID: 20933420

Authors

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

Journal

Current biology : CB

Publication Data

October 26, 2010

Associated Grants

  • Agency: NIH HHS, Id: 1DP2OD006486
  • Agency: NIDDK NIH HHS, Id: DK074398
  • Agency: NIDDK NIH HHS, Id: DK075032
  • Agency: NIDDK NIH HHS, Id: DK083330
  • Agency: NIDDK NIH HHS, Id: DK60322
  • Agency: NIH HHS, Id: DP2 OD006486
  • Agency: NIAID NIH HHS, Id: P01 AI053194
  • Agency: NIAID NIH HHS, Id: P01AI53194
  • Agency: NIDDK NIH HHS, Id: P30 DK065988
  • Agency: NIDDK NIH HHS, Id: P30 DK065988
  • Agency: NIDDK NIH HHS, Id: R01 DK060322
  • Agency: NIDDK NIH HHS, Id: R01 DK074398
  • Agency: NIDDK NIH HHS, Id: R01 DK075032
  • Agency: NIDDK NIH HHS, Id: R01 DK083330

Mesh Terms

  • Animals
  • Body Fluids
  • Cell Line
  • Cellular Apoptosis Susceptibility Protein
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • Dogs
  • Gastrointestinal Tract
  • Genes, Recessive
  • Green Fluorescent Proteins
  • Homeostasis
  • Immunoprecipitation
  • Microscopy, Confocal
  • Mutation
  • Zebrafish