Mechanisms of prickle1a function in zebrafish epilepsy and retinal neurogenesis

Xue Mei; Shu Wu; Alexander G Bassuk; Diane C Slusarski

doi:10.1242/dmm.010793

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Mechanisms of prickle1a function in zebrafish epilepsy and retinal neurogenesis

Journal article

Open access

Peer reviewed

Mechanisms of prickle1a function in zebrafish epilepsy and retinal neurogenesis

Xue Mei, Shu Wu, Alexander G Bassuk and Diane C Slusarski

Disease models & mechanisms, Vol.6(3), pp.679-688

05/2013

DOI: 10.1242/dmm.010793

PMCID: PMC3634651

PMID: 23324328

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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.

Retina - drug effects

Retina - metabolism

Zebrafish Proteins - metabolism

Humans

Embryo, Nonmammalian - metabolism

Epilepsy - metabolism

LIM Domain Proteins - metabolism

Mutation - genetics

Zebrafish - embryology

Embryo, Nonmammalian - drug effects

Gene Knockdown Techniques

Dose-Response Relationship, Drug

Animals

Zebrafish - metabolism

Morpholinos - pharmacology

Neurogenesis - drug effects

Swimming

Adaptor Proteins, Signal Transducing - metabolism

Pentylenetetrazole - pharmacology

Details

Title: Subtitle: Mechanisms of prickle1a function in zebrafish epilepsy and retinal neurogenesis
Creators: Xue Mei - Department of Biology, University of Iowa, Iowa City, IA 52242, USA
Shu Wu
Alexander G Bassuk
Diane C Slusarski
Resource Type: Journal article
Publication Details: Disease models & mechanisms, Vol.6(3), pp.679-688
DOI: 10.1242/dmm.010793
PMID: 23324328
PMCID: PMC3634651
NLM abbreviation: Dis Model Mech
ISSN: 1754-8403
eISSN: 1754-8411
Publisher: England
Grant note: R01NS064159 / NINDS NIH HHS R01 NS064159 / NINDS NIH HHS
Language: English
Date published: 05/2013
Academic Unit: Neurology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Biology; Fraternal Order of Eagles Diabetes Research Center; Neurology (Pediatrics); Internal Medicine
Record Identifier: 9984070799702771

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