Identification of slit3 as a locus affecting nicotine preference in zebrafish and human smoking behaviour

eLife

Robert T Walton¹  Adrian R Martineau¹  David Joliffe¹  Muy-Teck Teh²  Teemu Palviainen³  Jaakko Kaprio⁴  Valerie Kuan⁵  Riva J Riley⁶  Judit García-González⁶  Caroline H Brennan⁶  Ari Sudwarts⁶  Alistair J Brock⁶  Matthew O Parker⁷  Derek L Stemple⁸  Elisabeth M Busch-Nentwich⁹ 

[1] Barts and The London School of Medicine and Dentistry, Blizard Institute, London, United Kingdom;Centre for Immunobiology and Regenerative Medicine, Institute of Dentistry, Barts and The London School of Medicine and Dentistry, London, United Kingdom;Institute for Molecular Medicine FIMM, HiLIFE, Helsinki, Finland;Institute for Molecular Medicine FIMM, HiLIFE, Helsinki, Finland;Department of Public Health, Faculty of Medicine, University of Helsinki, Helsinki, Finland;Institute of Cardiovascular Science, University College London, London, United Kingdom;School of Biological and Chemical Sciences, Queen Mary, University of London, London, United Kingdom;School of Pharmacy and Biomedical Science, University of Portsmouth, Portsmouth, United Kingdom;Wellcome Trust Sanger Institute, Cambridge, United Kingdom;Wellcome Trust Sanger Institute, Cambridge, United Kingdom;Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, United Kingdom;

关键词: slit3;    acoustic startle;    smoking;    conditioned place preference;    gene association;    nicotine;    Zebrafish;   

DOI  :  10.7554/eLife.51295

来源: publisher

【 摘 要 】

To facilitate smoking genetics research we determined whether a screen of mutagenized zebrafish for nicotine preference could predict loci affecting smoking behaviour. From 30 screened F3 sibling groups, where each was derived from an individual ethyl-nitrosurea mutagenized F0 fish, two showed increased or decreased nicotine preference. Out of 25 inactivating mutations carried by the F3 fish, one in the slit3 gene segregated with increased nicotine preference in heterozygous individuals. Focussed SNP analysis of the human SLIT3 locus in cohorts from UK (n=863) and Finland (n=1715) identified two variants associated with cigarette consumption and likelihood of cessation. Characterisation of slit3 mutant larvae and adult fish revealed decreased sensitivity to the dopaminergic and serotonergic antagonist amisulpride, known to affect startle reflex that is correlated with addiction in humans, and increased htr1aa mRNA expression in mutant larvae. No effect on neuronal pathfinding was detected. These findings reveal a role for SLIT3 in development of pathways affecting responses to nicotine in zebrafish and smoking in humans.

【 授权许可】

CC BY