Epilepsy and Altered Interneuron Development in the Flathead([italic]fh/fh[/italic]) Rat Are Associated with a Mutation in the Gene Encoding Citron Kinase.
Abstract number :
3.028
Submission category :
Year :
2001
Submission ID :
181
Source :
www.aesnet.org
Presentation date :
12/1/2001 12:00:00 AM
Published date :
Dec 1, 2001, 06:00 AM
Authors :
M.R. Sarkisian, Physiology and Neurobiology, University of Connecticut, Storrs, CT; W. Li, MD, PhD, Physiology and Neurobiology, University of Connecticut, Storrs, CT; S.R. D[ssquote]Mello, PhD, Molecular and Cell Biology, University of Texas at Dallas, R
RATIONALE: Analysis of spontaneous mutations in rodents and humans have lead to the identification of genes and proteins essential to the development of the neocortex and CNS in general. These mutations are often associated with focal or widespread cortical malformations and epilepsy. The Flathead ([italic]fh/fh[/italic]) mutation is a spontaneous, autosomal recessive mutation in rat which results in a dramatically reduced cerebral cortex and cerebellum. In previous reports we have shown that the molecular mutation maps to the distal arm of chromosome 12 and that affected rats display early onset seizures, dramatic alterations in interneuron development, increases in cell death during neurogenesis and multinucleate neurons throughout neocortex. Therefore, the goal of this study was to identify the mutated gene underlying the [italic]fh/fh[/italic] phenotype.
METHODS: We used multiple techniques including gene cloning and sequencing, western blotting, and immunocytochemistry.
RESULTS: Here we show that the [italic]fh[/italic] mutation is caused by a base-pair deletion in exon 1 of the gene encoding Citron Kinase (Citron-K). Western blot analysis shows that the Citron-K protein is absent in [italic]fh/fh[/italic]. In addition, we show with immunocytochemistry that Citron-K protein is distributed in discrete puncta, primarily along the ventricular zone surface of embryonic cortex and within the external granule cell layer of developing cerebellum. Mutants lack the these puncta of Citron protein in both proliferative zones.
CONCLUSIONS: The Citron-K protein is thus essential to normal cytokinesis in certain CNS neuroblasts, and this cytokinetic regulation appears essential to the survival and fates of newly generated cells. Moreover, future studies will require an understanding of how a loss of Citron-K ultimately leads to epileptogenesis in the [italic]fh/fh[/italic] brain.
Support: NIH grant MH5624 and March of Dimes grant 0307 to JJL.