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PMID:21835885

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Citation

Rossetto, MG, Zanarella, E, Orso, G, Scorzeto, M, Megighian, A, Kumar, V, Delgado-Escueta, AV and Daga, A (2011) Defhc1.1, a homologue of the juvenile myoclonic gene EFHC1, modulates architecture and basal activity of the neuromuscular junction in Drosophila. Hum. Mol. Genet. 20:4248-57

Abstract

Mutations in the EFHC1 gene have been linked to juvenile myoclonic epilepsy. To understand EFHC1 function in vivo, we generated knockout Drosophila for the fly homolog Defhc1.1. We found that the neuromuscular junction synapse of Defhc1.1 mutants displays an increased number of satellite boutons resulting in increased spontaneous neurotransmitter release. Defhc1.1 binds to microtubules in vitro and overlaps in vivo with axonal and synaptic microtubules. Elimination of Defhc1.1 from synaptic terminals reduces the number of microtubule loops, suggesting that Defhc1.1 is a negative regulator of microtubule dynamics. In fact, pharmacological treatment of Defhc1.1 mutants with vinblastine, an inhibitor of microtubule dynamics, suppresses the satellite bouton phenotype. Furthermore, Defhc1.1 mutants display overgrowth of the dendritic arbor and Defhc1.1 overexpression reduces dendrite elaboration. These results suggest that Defhc1.1 functions as an inhibitor of neurite growth by finely tuning the microtubule cytoskeleton dynamics and that EFHC1-dependent juvenile myoclonic epilepsy may result from augmented spontaneous neurotransmitter release due to overgrowth of neuronal processes.

Links

PubMed Online version:10.1093/hmg/ddr352

Keywords

Animals; Calcium-Binding Proteins/chemistry; Calcium-Binding Proteins/genetics; Dendritic Spines/metabolism; Drosophila Proteins/genetics; Drosophila Proteins/metabolism; Drosophila melanogaster/metabolism; Evoked Potentials; Microtubule Proteins/genetics; Microtubule Proteins/metabolism; Microtubules/metabolism; Mutation/genetics; Myoclonic Epilepsy, Juvenile/genetics; Myoclonic Epilepsy, Juvenile/pathology; Neurotransmitter Agents/secretion; Presynaptic Terminals/metabolism; Protein Binding; Sequence Homology, Amino Acid

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

DROME:Q9VXP5

located_in

GO:0043195: terminal bouton

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

DROME:Q9VXP5

located_in

GO:0030425: dendrite

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

DROME:Q9VXP5

colocalizes_with

GO:0005874: microtubule

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

DROME:Q9VXP5

located_in

GO:0043025: neuronal cell body

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

DROME:Q9VXP5

involved_in

GO:0051124: synaptic assembly at neuromuscular junction

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:Q9VXP5

involved_in

GO:0048814: regulation of dendrite morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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