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Edited by John E. Dowling, Harvard University, Cambridge, MA, and approved September 16, 2009 (received for review July 23, 2009)
Abstract
Tobacco use is predicted to result in over 1 billion deaths worldwide by the end of the 21st century. How genetic variation contributes to the observed differential predisposition in the human population to drug dependence is unknown. The zebrafish (Danio rerio) is an emerging vertebrate model system for understanding the genetics of behavior. We developed a nicotine behavioral assay in zebrafish and applied it in a forward genetic screen using gene-breaking transposon mutagenesis. We used this method to molecularly characterize bdav/cct8 and hbog/gabbr1.2 as mutations with altered nicotine response. Each have a single human ortholog, identifying two points for potential scientific, diagnostic, and drug development for nicotine biology and cessation therapeutics. We show this insertional method generates mutant alleles that are reversible through Cre-mediated recombination, representing a conditional mutation system for the zebrafish. The combination of this reporter-tagged insertional mutagen approach and zebrafish provides a powerful platform for a rich array of questions amenable to genetic-based scientific inquiry, including the basis of behavior, epigenetics, plasticity, stress, memory, and learning.
Footnotes
- 1To whom correspondence should be addressed. E-mail: ekker.stephen{at}mayo.edu
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Author contributions: A.M.P., D.B., M.J.T., and S.C.E. designed research; A.M.P., V.M.B., and G.L.M. performed research; D.B., S.S., S.E.W., S.R.M., and S.C.E. contributed new reagents/analytic tools; A.M.P. and K.J.C. analyzed data; and A.M.P. and S.C.E. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Nicotine response genetics in the zebrafish
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