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Wwox deficiency leads to neurodevelopmental and degenerative neuropathies and glycogen synthase kinase 3β-mediated epileptic seizure activity in mice
Human WWOX gene resides in the chromosomal common fragile site FRA16D and encodes a tumor suppressor WW domain-containing oxidoreductase. Loss-of-function mutations in both alleles of WWOX gene lead to autosomal recessive abnormalities in pediatric patients from consanguineous families, including mi...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6990504/ https://www.ncbi.nlm.nih.gov/pubmed/32000863 http://dx.doi.org/10.1186/s40478-020-0883-3 |
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author | Cheng, Ya-Yun Chou, Ying-Tsen Lai, Feng-Jie Jan, Ming-Shiou Chang, Tsung-Hao Jou, I-Ming Chen, Pei-Shiuan Lo, Jui-Yen Huang, Shiang-Suo Chang, Nan-Shan Liou, Yung-Tsai Hsu, Po-Chih Cheng, Hui-Ching Lin, Yee-Shin Hsu, Li-Jin |
author_facet | Cheng, Ya-Yun Chou, Ying-Tsen Lai, Feng-Jie Jan, Ming-Shiou Chang, Tsung-Hao Jou, I-Ming Chen, Pei-Shiuan Lo, Jui-Yen Huang, Shiang-Suo Chang, Nan-Shan Liou, Yung-Tsai Hsu, Po-Chih Cheng, Hui-Ching Lin, Yee-Shin Hsu, Li-Jin |
author_sort | Cheng, Ya-Yun |
collection | PubMed |
description | Human WWOX gene resides in the chromosomal common fragile site FRA16D and encodes a tumor suppressor WW domain-containing oxidoreductase. Loss-of-function mutations in both alleles of WWOX gene lead to autosomal recessive abnormalities in pediatric patients from consanguineous families, including microcephaly, cerebellar ataxia with epilepsy, mental retardation, retinal degeneration, developmental delay and early death. Here, we report that targeted disruption of Wwox gene in mice causes neurodevelopmental disorders, encompassing abnormal neuronal differentiation and migration in the brain. Cerebral malformations, such as microcephaly and incomplete separation of the hemispheres by a partial interhemispheric fissure, neuronal disorganization and heterotopia, and defective cerebellar midline fusion are observed in Wwox(−/−) mice. Degenerative alterations including severe hypomyelination in the central nervous system, optic nerve atrophy, Purkinje cell loss and granular cell apoptosis in the cerebellum, and peripheral nerve demyelination due to Schwann cell apoptosis correspond to reduced amplitudes and a latency prolongation of transcranial motor evoked potentials, motor deficits and gait ataxia in Wwox(−/−) mice. Wwox gene ablation leads to the occurrence of spontaneous epilepsy and increased susceptibility to pilocarpine- and pentylenetetrazol (PTZ)-induced seizures in preweaning mice. We determined that a significantly increased activation of glycogen synthase kinase 3β (GSK3β) occurs in Wwox(−/−) mouse cerebral cortex, hippocampus and cerebellum. Inhibition of GSK3β by lithium ion significantly abolishes the onset of PTZ-induced seizure in Wwox(−/−) mice. Together, our findings reveal that the neurodevelopmental and neurodegenerative deficits in Wwox knockout mice strikingly recapitulate the key features of human neuropathies, and that targeting GSK3β with lithium ion ameliorates epilepsy. |
format | Online Article Text |
id | pubmed-6990504 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-69905042020-02-03 Wwox deficiency leads to neurodevelopmental and degenerative neuropathies and glycogen synthase kinase 3β-mediated epileptic seizure activity in mice Cheng, Ya-Yun Chou, Ying-Tsen Lai, Feng-Jie Jan, Ming-Shiou Chang, Tsung-Hao Jou, I-Ming Chen, Pei-Shiuan Lo, Jui-Yen Huang, Shiang-Suo Chang, Nan-Shan Liou, Yung-Tsai Hsu, Po-Chih Cheng, Hui-Ching Lin, Yee-Shin Hsu, Li-Jin Acta Neuropathol Commun Research Human WWOX gene resides in the chromosomal common fragile site FRA16D and encodes a tumor suppressor WW domain-containing oxidoreductase. Loss-of-function mutations in both alleles of WWOX gene lead to autosomal recessive abnormalities in pediatric patients from consanguineous families, including microcephaly, cerebellar ataxia with epilepsy, mental retardation, retinal degeneration, developmental delay and early death. Here, we report that targeted disruption of Wwox gene in mice causes neurodevelopmental disorders, encompassing abnormal neuronal differentiation and migration in the brain. Cerebral malformations, such as microcephaly and incomplete separation of the hemispheres by a partial interhemispheric fissure, neuronal disorganization and heterotopia, and defective cerebellar midline fusion are observed in Wwox(−/−) mice. Degenerative alterations including severe hypomyelination in the central nervous system, optic nerve atrophy, Purkinje cell loss and granular cell apoptosis in the cerebellum, and peripheral nerve demyelination due to Schwann cell apoptosis correspond to reduced amplitudes and a latency prolongation of transcranial motor evoked potentials, motor deficits and gait ataxia in Wwox(−/−) mice. Wwox gene ablation leads to the occurrence of spontaneous epilepsy and increased susceptibility to pilocarpine- and pentylenetetrazol (PTZ)-induced seizures in preweaning mice. We determined that a significantly increased activation of glycogen synthase kinase 3β (GSK3β) occurs in Wwox(−/−) mouse cerebral cortex, hippocampus and cerebellum. Inhibition of GSK3β by lithium ion significantly abolishes the onset of PTZ-induced seizure in Wwox(−/−) mice. Together, our findings reveal that the neurodevelopmental and neurodegenerative deficits in Wwox knockout mice strikingly recapitulate the key features of human neuropathies, and that targeting GSK3β with lithium ion ameliorates epilepsy. BioMed Central 2020-01-30 /pmc/articles/PMC6990504/ /pubmed/32000863 http://dx.doi.org/10.1186/s40478-020-0883-3 Text en © The Author(s). 2020 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Cheng, Ya-Yun Chou, Ying-Tsen Lai, Feng-Jie Jan, Ming-Shiou Chang, Tsung-Hao Jou, I-Ming Chen, Pei-Shiuan Lo, Jui-Yen Huang, Shiang-Suo Chang, Nan-Shan Liou, Yung-Tsai Hsu, Po-Chih Cheng, Hui-Ching Lin, Yee-Shin Hsu, Li-Jin Wwox deficiency leads to neurodevelopmental and degenerative neuropathies and glycogen synthase kinase 3β-mediated epileptic seizure activity in mice |
title | Wwox deficiency leads to neurodevelopmental and degenerative neuropathies and glycogen synthase kinase 3β-mediated epileptic seizure activity in mice |
title_full | Wwox deficiency leads to neurodevelopmental and degenerative neuropathies and glycogen synthase kinase 3β-mediated epileptic seizure activity in mice |
title_fullStr | Wwox deficiency leads to neurodevelopmental and degenerative neuropathies and glycogen synthase kinase 3β-mediated epileptic seizure activity in mice |
title_full_unstemmed | Wwox deficiency leads to neurodevelopmental and degenerative neuropathies and glycogen synthase kinase 3β-mediated epileptic seizure activity in mice |
title_short | Wwox deficiency leads to neurodevelopmental and degenerative neuropathies and glycogen synthase kinase 3β-mediated epileptic seizure activity in mice |
title_sort | wwox deficiency leads to neurodevelopmental and degenerative neuropathies and glycogen synthase kinase 3β-mediated epileptic seizure activity in mice |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6990504/ https://www.ncbi.nlm.nih.gov/pubmed/32000863 http://dx.doi.org/10.1186/s40478-020-0883-3 |
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