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PMID:23324328

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Citation

Mei, X, Wu, S, Bassuk, AG and Slusarski, DC (2013) Mechanisms of prickle1a function in zebrafish epilepsy and retinal neurogenesis. Dis Model Mech 6:679-88

Abstract

Epilepsy is a complex neurological disorder characterized by unprovoked seizures. The etiology is heterogeneous with both genetic and environmental causes. Genes that regulate neurotransmitters and ion channels in the central nervous system have been associated with epilepsy. However, a recent screening in human epilepsy patients identified mutations in the PRICKLE1 (PK1) locus, highlighting a potentially novel mechanism underlying seizures. PK1 is a core component of the planar cell polarity network that regulates tissue polarity. Zebrafish studies have shown that Pk1 coordinates cell movement, neuronal migration and axonal outgrowth during embryonic development. Yet how dysfunction of Pk1 relates to epilepsy is unknown. To address the mechanism underlying epileptogenesis, we used zebrafish to characterize Pk1a function and epilepsy-related mutant forms. We show that knockdown of pk1a activity sensitizes zebrafish larva to a convulsant drug. To model defects in the central nervous system, we used the retina and found that pk1a knockdown induces neurite outgrowth defects; yet visual function is maintained. Furthermore, we characterized the functional and biochemical properties of the PK1 mutant forms identified in human patients. Functional analyses demonstrate that the wild-type Pk1a partially suppresses the gene knockdown retinal defects but not the mutant forms. Biochemical analysis reveals increased ubiquitylation of one mutant form and decreased translational efficiency of another mutant form compared with the wild-type Pk1a. Taken together, our results indicate that mutation of human PK1 could lead to defects in neurodevelopment and signal processing, providing insight into seizure predisposition in these patients.

Links

PubMed PMC3634651 Online version:10.1242/dmm.010793

Keywords

Adaptor Proteins, Signal Transducing/metabolism; Animals; Dose-Response Relationship, Drug; Embryo, Nonmammalian/drug effects; Embryo, Nonmammalian/metabolism; Epilepsy/metabolism; Gene Knockdown Techniques; Humans; LIM Domain Proteins/metabolism; Morpholinos/pharmacology; Mutation/genetics; Neurogenesis/drug effects; Pentylenetetrazole/pharmacology; Retina/drug effects; Retina/metabolism; Swimming; Zebrafish/embryology; Zebrafish/metabolism; Zebrafish Proteins/metabolism

Significance

Annotations

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

DANRE:B3DGT8

involved_in

GO:0031175: neuron projection development

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-081220-3

P

Seeded From UniProt

complete

DANRE:B3DGT8

involved_in

GO:0031175: neuron projection development

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-060209-7

P

Seeded From UniProt

complete

DANRE:B3DGT8

involved_in

GO:0003407: neural retina development

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-060209-7

P

Seeded From UniProt

complete

DANRE:F1Q6J9

involved_in

GO:0031175: neuron projection development

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-081220-3

P

Seeded From UniProt

complete

DANRE:F1Q6J9

involved_in

GO:0031175: neuron projection development

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-060209-7

P

Seeded From UniProt

complete

DANRE:F1Q6J9

involved_in

GO:0003407: neural retina development

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-060209-7

P

Seeded From UniProt

complete

DANRE:Q7ZZC5

involved_in

GO:0031175: neuron projection development

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-081220-3

P

Seeded From UniProt

complete

DANRE:Q7ZZC5

involved_in

GO:0031175: neuron projection development

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-060209-7

P

Seeded From UniProt

complete

DANRE:Q7ZZC5

involved_in

GO:0003407: neural retina development

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-060209-7

P

Seeded From UniProt

complete

DANRE:Q6WGK5

involved_in

GO:0031175: neuron projection development

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-081220-3

P

Seeded From UniProt

complete

DANRE:Q6WGK5

involved_in

GO:0031175: neuron projection development

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-060209-7

P

Seeded From UniProt

complete

DANRE:Q6WGK5

involved_in

GO:0003407: neural retina development

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-060209-7

P

Seeded From UniProt

complete

Notes

See also

References

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