Journal
CURRENT BIOLOGY
Volume 20, Issue 20, Pages 1840-1845Publisher
CELL PRESS
DOI: 10.1016/j.cub.2010.09.012
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Funding
- European Molecular Biology Organization
- Human Frontier Science Program
- Cystic Fibrosis Foundation (CFF) [0810]
- National Institutes of Health (NIH) [1DP2OD006486, DK083330, DK074398, P01 AI53194, P30 DK065988, DK60322, DK075032]
- CFF
- Packard Foundation
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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 cse1I 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 Cse1I 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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