Originally published as Genetics Published Articles Ahead of Print on April 15, 2007.

Genetics, Vol. 176, 947-956, June 2007, Copyright © 2007
doi:10.1534/genetics.106.069781

The Early Developmental Gene Semaphorin 5c Contributes to Olfactory Behavior in Adult Drosophila

Stephanie M. Rollmann^*,,1, Akihiko Yamamoto^*,, Tim Goossens, Liesbeth Zwarts, Zsuzsanna Callaerts-Végh, Patrick Callaerts^,**, Koenraad Norga^,, Trudy F. C. Mackay^, and Robert R. H. Anholt^*,,,2

^* Department of Zoology, Department of Genetics and W. M. Keck Center for Behavioral Biology, North Carolina State University, Raleigh, North Carolina 27695, Laboratory of Developmental Genetics, Center for Human Genetics, B-3000 Leuven, Belgium, Zoological Institute, Department of Biology, B-3000 Leuven, Belgium, ^** Laboratory of Biological Psychology, B-3000 Leuven, Belgium and Children's Hospital, B-3000 Leuven, Belgium

² Corresponding author: W. M. Keck Center for Behavioral Biology, Campus Box 7617, North Carolina State University, Raleigh, NC 27695-7617.
E-mail: anholt{at}ncsu.edu

Behaviors are complex traits influenced by multiple pleiotropic genes. Understanding the mechanisms that give rise to complex behaviors requires an understanding of how variation in transcriptional regulation shapes nervous system development and how variation in brain structure influences an organism's ability to respond to its environment. To begin to address this problem, we used olfactory behavior in Drosophila melanogaster as a model and showed that a hypomorphic transposon-mediated mutation of the early developmental gene Semaphorin-5c (Sema-5c) results in aberrant behavioral responses to the repellant odorant benzaldehyde. We fine mapped this effect to the Sema-5c locus using deficiency mapping, phenotypic reversion through P-element excision, and transgenic rescue. Morphometric analysis of this Sema-5c allele reveals subtle neuroanatomical changes in the brain with a reduction in the size of the ellipsoid body. High-density oligonucleotide expression microarrays identified 50 probe sets with altered transcriptional regulation in the Sema-5c background and quantitative complementation tests identified epistatic interactions between nine of these coregulated genes and the transposon-disrupted Sema-5c gene. Our results demonstrate how hypomorphic mutation of an early developmental gene results in genomewide transcriptional consequences and alterations in brain structure accompanied by profound impairment of adult behavior.

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