QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, March 14, 2007, 27(11):2927-2937; doi:10.1523/JNEUROSCI.3944-06.2007

This Article Full Text Full Text (PDF) Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via ISI Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Song, J. Articles by Tanouye, M. Search for Related Content PubMed PubMed Citation Articles by Song, J. Articles by Tanouye, M. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Substance via MeSH Medline Plus Health Information Seizures

 Previous Article  |  Next Article 

Neurobiology of Disease
Seizure Suppression by top1 Mutations in Drosophila

Juan Song,^1,2 Joyce Hu,^1,2 and Mark Tanouye^1,2

¹Division of Insect Biology, Department of Environmental Science, Policy and Management, and ²Division of Neurobiology, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California 94720

Correspondence should be addressed to Juan Song, Department of Molecular and Cell Biology, Life Sciences Addition, Room 131, University of California, Berkeley, CA 94720. Email: juansong{at}berkeley.edu

DNA topoisomerase I is an essential nuclear enzyme involved in resolving the torsional stress associated with DNA replication, transcription, and chromatin condensation. Here we report the discovery of a seizure-suppressor mutant, top1^JS, which suppresses seizures in a Drosophila model of human epilepsy. A P-element mutagenesis screen using easily shocked seizure-sensitive mutant as a genetic background identified top1^JS, which plays a novel role in regulating nervous system excitability. Plasmid rescue, excision, complementation, and sequencing analyses verified that top1^JS results from a P-element insertion in the 5' untranslated region. Quantitative reverse transcription analysis on wild-type and mutant fly heads showed that the top1^JS mutation causes reduced transcription level in the CNS, suggesting a partial loss-of-function mutation. Electrophysiological experiments revealed normal seizure thresholds in top1^JS mutants, which are different from other seizure suppressors identified previously, suggesting a novel mechanism underlying seizure suppression by top1^JS. The pharmacological camptothecin feeding experiment and cell death analysis suggested that the seizure suppression by top1^JS may occur via increased neuronal apoptosis. Furthermore, overexpression of the DIAP1 (Drosophila inhibitor of apoptosis 1) gene rescues top1^JS suppression, providing additional support for a neural apoptosis suppression mechanism. The top1^JS mutation is the first viable partial loss-of-function mutation identified in higher eukaryotes, and the results presented here point to a novel function for topo I in construction and/or maintenance of circuits required for seizure propagation in vivo.

Key words: topoisomerase I; seizure; suppression; camptothecin; epilepsy; Drosophila

---

Received May 11, 2006; revised Jan. 9, 2007; accepted Feb. 4, 2007.

Correspondence should be addressed to Juan Song, Department of Molecular and Cell Biology, Life Sciences Addition, Room 131, University of California, Berkeley, CA 94720. Email: juansong{at}berkeley.edu

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help