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Genetic interactions among cortical malformation genes that influence susceptibility to convulsions in C. elegans

Locke, Cody J. and Williams, Shelli N. and Schwarz, Erich M. and Caldwell, Guy A. and Caldwell, Kim A. (2006) Genetic interactions among cortical malformation genes that influence susceptibility to convulsions in C. elegans. Brain Research, 1120 (1). pp. 23-34. ISSN 0006-8993. https://resolver.caltech.edu/CaltechAUTHORS:20170408-171947325

[img] PDF (Supplemental Table 1.) - Supplemental Material
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[img] Image (JPEG) (Supplemental Fig. 1. The N-terminal block of high similarity of NUD-2/R11A5.2 to other NudE homologs listed in Supplemental Table 1) - Supplemental Material
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[img] Image (JPEG) (Supplemental Fig. 2. The C-terminal block of high similarity of NUD-2/R11A5.2 to other NudE homologs) - Supplemental Material
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[img] Image (JPEG) (Supplemental Fig. 3. In vivo expression of GFP translational fusion with NUD-2 in transgenic C. elegans. Expression is within the ventral nerve cord (shown in Fig. 2B) as well as in the pharynx (A) and vulva muscles (B)) - Supplemental Material
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[img] Image (JPEG) (Supplemental Fig. 4. Modulation of RNAi-induced phenotypes via different concentrations of β-lactose) - Supplemental Material
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[img] Image (JPEG) (Supplemental Fig. 5. Depletion of LIS-1-related targets by RNAi enhances the convulsive phenotype of a GABA synthesis mutant, unc-25 (e156).) - Supplemental Material
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Abstract

Epilepsy is estimated to affect 1–2% of the world population, yet remains poorly understood at a molecular level. We have previously established the roundworm Caenorhabditis elegans as a model for investigating genetic susceptibilities to seizure-like convulsions in vivo. Here we investigate the behavioral consequences of decreasing the activity of nematode gene homologs within the LIS1 pathway that are associated with a human cortical malformation termed lissencephaly. Bioinformatic analysis revealed the nud-2 gene, encoding the worm homolog of mammalian effectors of LIS1, termed NDE1 and NDEL1. Phenotypic analysis of animals targeted by RNA interference (RNAi) was performed using a pentylenetetrazole (PTZ) exposure paradigm to induce convulsions. Worms depleted for LIS1 pathway components (NUD-1, NUD-2, DHC-1, CDK-5, and CDKA-1) exhibited significant convulsions following PTZ and RNAi treatment. Strains harboring fluorescent markers for GABAergic neuronal architecture and synaptic vesicle trafficking were employed to discern putative mechanisms accounting for observed convulsion behaviors. We found that depletion of LIS1 pathway components resulted in defective GABA synaptic vesicle trafficking. We also utilized combinations of specific genetic backgrounds to create a sensitized state for convulsion susceptibility and discovered that convulsion effects were significantly enhanced when LIS-1 and other pathway components were compromised within the same animals. Thus, interactions among gene products with LIS-1 may mediate intrinsic thresholds of neuronal synchrony.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1016/j.brainres.2006.08.067DOIArticle
http://www.wormbase.org/get?doi=10.1016/j.brainres.2006.08.067Related ItemNematode biology and genomics data
ORCID:
AuthorORCID
Schwarz, Erich M.0000-0003-3151-4381
Additional Information:© 2006 Elsevier. Accepted 20 August 2006, Available online 22 September 2006. We would like to thank all members of the Caldwell Laboratory, especially Lindsay Faircloth and Stacey Fox, for their collegiality and teamwork, and Paul Sternberg for support. We acknowledge the generosity of Yishi Jin and Erik Jorgensen for sharing GFP marker strains used in this study. C. elegans strains came from the Caenorhabditis Genetics Center which is funded by the NIH NCRR. Sequencing was performed using equipment funded by the NSF (DBI-0070351). This work was funded by a Basil O'Connor Scholar Award from the March of Dimes and a CAREER Award from the National Science Foundation (0237956) to GAC. Support for an undergraduate researcher (CJL) on this work came from a Howard Hughes Medical Institute Undergraduate Science Education grant to The University of Alabama.
Funders:
Funding AgencyGrant Number
NIHUNSPECIFIED
NSFDBI-0070351
March of Dimes FoundationUNSPECIFIED
NSFIOS-0237956
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Subject Keywords:Epilepsy; Genetics; Lissencephaly; Caenorhabditis elegans; RNAi
Issue or Number:1
Record Number:CaltechAUTHORS:20170408-171947325
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20170408-171947325
Official Citation:Cody J. Locke, Shelli N. Williams, Erich M. Schwarz, Guy A. Caldwell, Kim A. Caldwell, Genetic interactions among cortical malformation genes that influence susceptibility to convulsions in C. elegans, Brain Research, Volume 1120, Issue 1, 2006, Pages 23-34, ISSN 0006-8993, https://doi.org/10.1016/j.brainres.2006.08.067. (http://www.sciencedirect.com/science/article/pii/S0006899306025443)
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:76326
Collection:CaltechAUTHORS
Deposited By: 1Science Import
Deposited On:13 Mar 2018 18:39
Last Modified:29 Oct 2019 21:49

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