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Mechanisms of prickle1a function in zebrafish epilepsy and retinal neurogenesis
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 scree...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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The Company of Biologists Limited
2013
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3634651/ https://www.ncbi.nlm.nih.gov/pubmed/23324328 http://dx.doi.org/10.1242/dmm.010793 |
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author | Mei, Xue Wu, Shu Bassuk, Alexander G. Slusarski, Diane C. |
author_facet | Mei, Xue Wu, Shu Bassuk, Alexander G. Slusarski, Diane C. |
author_sort | Mei, Xue |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-3634651 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | The Company of Biologists Limited |
record_format | MEDLINE/PubMed |
spelling | pubmed-36346512013-06-19 Mechanisms of prickle1a function in zebrafish epilepsy and retinal neurogenesis Mei, Xue Wu, Shu Bassuk, Alexander G. Slusarski, Diane C. Dis Model Mech Research Article 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. The Company of Biologists Limited 2013-05 2013-01-11 /pmc/articles/PMC3634651/ /pubmed/23324328 http://dx.doi.org/10.1242/dmm.010793 Text en © 2013. Published by The Company of Biologists Ltd This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial Share Alike License (http://creativecommons.org/licenses/by-nc-sa/3.0), which permits unrestricted non-commercial use, distribution and reproduction in any medium provided that the original work is properly cited and all further distributions of the work or adaptation are subject to the same Creative Commons License terms. |
spellingShingle | Research Article Mei, Xue Wu, Shu Bassuk, Alexander G. Slusarski, Diane C. Mechanisms of prickle1a function in zebrafish epilepsy and retinal neurogenesis |
title | Mechanisms of prickle1a function in zebrafish epilepsy and retinal neurogenesis |
title_full | Mechanisms of prickle1a function in zebrafish epilepsy and retinal neurogenesis |
title_fullStr | Mechanisms of prickle1a function in zebrafish epilepsy and retinal neurogenesis |
title_full_unstemmed | Mechanisms of prickle1a function in zebrafish epilepsy and retinal neurogenesis |
title_short | Mechanisms of prickle1a function in zebrafish epilepsy and retinal neurogenesis |
title_sort | mechanisms of prickle1a function in zebrafish epilepsy and retinal neurogenesis |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3634651/ https://www.ncbi.nlm.nih.gov/pubmed/23324328 http://dx.doi.org/10.1242/dmm.010793 |
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