Cargando…
CUX2 deficiency causes facilitation of excitatory synaptic transmission onto hippocampus and increased seizure susceptibility to kainate
CUX2 gene encodes a transcription factor that controls neuronal proliferation, dendrite branching and synapse formation, locating at the epilepsy-associated chromosomal region 12q24 that we previously identified by a genome-wide association study (GWAS) in Japanese population. A CUX2 recurrent de no...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9114133/ https://www.ncbi.nlm.nih.gov/pubmed/35581205 http://dx.doi.org/10.1038/s41598-022-10715-w |
_version_ | 1784709717110554624 |
---|---|
author | Suzuki, Toshimitsu Tatsukawa, Tetsuya Sudo, Genki Delandre, Caroline Pai, Yun Jin Miyamoto, Hiroyuki Raveau, Matthieu Shimohata, Atsushi Ohmori, Iori Hamano, Shin-ichiro Haginoya, Kazuhiro Uematsu, Mitsugu Takahashi, Yukitoshi Morimoto, Masafumi Fujimoto, Shinji Osaka, Hitoshi Oguni, Hirokazu Osawa, Makiko Ishii, Atsushi Hirose, Shinichi Kaneko, Sunao Inoue, Yushi Moore, Adrian Walton Yamakawa, Kazuhiro |
author_facet | Suzuki, Toshimitsu Tatsukawa, Tetsuya Sudo, Genki Delandre, Caroline Pai, Yun Jin Miyamoto, Hiroyuki Raveau, Matthieu Shimohata, Atsushi Ohmori, Iori Hamano, Shin-ichiro Haginoya, Kazuhiro Uematsu, Mitsugu Takahashi, Yukitoshi Morimoto, Masafumi Fujimoto, Shinji Osaka, Hitoshi Oguni, Hirokazu Osawa, Makiko Ishii, Atsushi Hirose, Shinichi Kaneko, Sunao Inoue, Yushi Moore, Adrian Walton Yamakawa, Kazuhiro |
author_sort | Suzuki, Toshimitsu |
collection | PubMed |
description | CUX2 gene encodes a transcription factor that controls neuronal proliferation, dendrite branching and synapse formation, locating at the epilepsy-associated chromosomal region 12q24 that we previously identified by a genome-wide association study (GWAS) in Japanese population. A CUX2 recurrent de novo variant p.E590K has been described in patients with rare epileptic encephalopathies and the gene is a candidate for the locus, however the mutation may not be enough to generate the genome-wide significance in the GWAS and whether CUX2 variants appear in other types of epilepsies and physiopathological mechanisms are remained to be investigated. Here in this study, we conducted targeted sequencings of CUX2, a paralog CUX1 and its short isoform CASP harboring a unique C-terminus on 271 Japanese patients with a variety of epilepsies, and found that multiple CUX2 missense variants, other than the p.E590K, and some CASP variants including a deletion, predominantly appeared in patients with temporal lobe epilepsy (TLE). The CUX2 variants showed abnormal localization in human cell culture analysis. While wild-type CUX2 enhances dendritic arborization in fly neurons, the effect was compromised by some of the variants. Cux2- and Casp-specific knockout mice both showed high susceptibility to kainate, increased excitatory cell number in the entorhinal cortex, and significant enhancement in glutamatergic synaptic transmission to the hippocampus. CASP and CUX2 proteins physiologically bound to each other and co-expressed in excitatory neurons in brain regions including the entorhinal cortex. These results suggest that CUX2 and CASP variants contribute to the TLE pathology through a facilitation of excitatory synaptic transmission from entorhinal cortex to hippocampus. |
format | Online Article Text |
id | pubmed-9114133 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-91141332022-05-19 CUX2 deficiency causes facilitation of excitatory synaptic transmission onto hippocampus and increased seizure susceptibility to kainate Suzuki, Toshimitsu Tatsukawa, Tetsuya Sudo, Genki Delandre, Caroline Pai, Yun Jin Miyamoto, Hiroyuki Raveau, Matthieu Shimohata, Atsushi Ohmori, Iori Hamano, Shin-ichiro Haginoya, Kazuhiro Uematsu, Mitsugu Takahashi, Yukitoshi Morimoto, Masafumi Fujimoto, Shinji Osaka, Hitoshi Oguni, Hirokazu Osawa, Makiko Ishii, Atsushi Hirose, Shinichi Kaneko, Sunao Inoue, Yushi Moore, Adrian Walton Yamakawa, Kazuhiro Sci Rep Article CUX2 gene encodes a transcription factor that controls neuronal proliferation, dendrite branching and synapse formation, locating at the epilepsy-associated chromosomal region 12q24 that we previously identified by a genome-wide association study (GWAS) in Japanese population. A CUX2 recurrent de novo variant p.E590K has been described in patients with rare epileptic encephalopathies and the gene is a candidate for the locus, however the mutation may not be enough to generate the genome-wide significance in the GWAS and whether CUX2 variants appear in other types of epilepsies and physiopathological mechanisms are remained to be investigated. Here in this study, we conducted targeted sequencings of CUX2, a paralog CUX1 and its short isoform CASP harboring a unique C-terminus on 271 Japanese patients with a variety of epilepsies, and found that multiple CUX2 missense variants, other than the p.E590K, and some CASP variants including a deletion, predominantly appeared in patients with temporal lobe epilepsy (TLE). The CUX2 variants showed abnormal localization in human cell culture analysis. While wild-type CUX2 enhances dendritic arborization in fly neurons, the effect was compromised by some of the variants. Cux2- and Casp-specific knockout mice both showed high susceptibility to kainate, increased excitatory cell number in the entorhinal cortex, and significant enhancement in glutamatergic synaptic transmission to the hippocampus. CASP and CUX2 proteins physiologically bound to each other and co-expressed in excitatory neurons in brain regions including the entorhinal cortex. These results suggest that CUX2 and CASP variants contribute to the TLE pathology through a facilitation of excitatory synaptic transmission from entorhinal cortex to hippocampus. Nature Publishing Group UK 2022-05-17 /pmc/articles/PMC9114133/ /pubmed/35581205 http://dx.doi.org/10.1038/s41598-022-10715-w Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Suzuki, Toshimitsu Tatsukawa, Tetsuya Sudo, Genki Delandre, Caroline Pai, Yun Jin Miyamoto, Hiroyuki Raveau, Matthieu Shimohata, Atsushi Ohmori, Iori Hamano, Shin-ichiro Haginoya, Kazuhiro Uematsu, Mitsugu Takahashi, Yukitoshi Morimoto, Masafumi Fujimoto, Shinji Osaka, Hitoshi Oguni, Hirokazu Osawa, Makiko Ishii, Atsushi Hirose, Shinichi Kaneko, Sunao Inoue, Yushi Moore, Adrian Walton Yamakawa, Kazuhiro CUX2 deficiency causes facilitation of excitatory synaptic transmission onto hippocampus and increased seizure susceptibility to kainate |
title | CUX2 deficiency causes facilitation of excitatory synaptic transmission onto hippocampus and increased seizure susceptibility to kainate |
title_full | CUX2 deficiency causes facilitation of excitatory synaptic transmission onto hippocampus and increased seizure susceptibility to kainate |
title_fullStr | CUX2 deficiency causes facilitation of excitatory synaptic transmission onto hippocampus and increased seizure susceptibility to kainate |
title_full_unstemmed | CUX2 deficiency causes facilitation of excitatory synaptic transmission onto hippocampus and increased seizure susceptibility to kainate |
title_short | CUX2 deficiency causes facilitation of excitatory synaptic transmission onto hippocampus and increased seizure susceptibility to kainate |
title_sort | cux2 deficiency causes facilitation of excitatory synaptic transmission onto hippocampus and increased seizure susceptibility to kainate |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9114133/ https://www.ncbi.nlm.nih.gov/pubmed/35581205 http://dx.doi.org/10.1038/s41598-022-10715-w |
work_keys_str_mv | AT suzukitoshimitsu cux2deficiencycausesfacilitationofexcitatorysynaptictransmissionontohippocampusandincreasedseizuresusceptibilitytokainate AT tatsukawatetsuya cux2deficiencycausesfacilitationofexcitatorysynaptictransmissionontohippocampusandincreasedseizuresusceptibilitytokainate AT sudogenki cux2deficiencycausesfacilitationofexcitatorysynaptictransmissionontohippocampusandincreasedseizuresusceptibilitytokainate AT delandrecaroline cux2deficiencycausesfacilitationofexcitatorysynaptictransmissionontohippocampusandincreasedseizuresusceptibilitytokainate AT paiyunjin cux2deficiencycausesfacilitationofexcitatorysynaptictransmissionontohippocampusandincreasedseizuresusceptibilitytokainate AT miyamotohiroyuki cux2deficiencycausesfacilitationofexcitatorysynaptictransmissionontohippocampusandincreasedseizuresusceptibilitytokainate AT raveaumatthieu cux2deficiencycausesfacilitationofexcitatorysynaptictransmissionontohippocampusandincreasedseizuresusceptibilitytokainate AT shimohataatsushi cux2deficiencycausesfacilitationofexcitatorysynaptictransmissionontohippocampusandincreasedseizuresusceptibilitytokainate AT ohmoriiori cux2deficiencycausesfacilitationofexcitatorysynaptictransmissionontohippocampusandincreasedseizuresusceptibilitytokainate AT hamanoshinichiro cux2deficiencycausesfacilitationofexcitatorysynaptictransmissionontohippocampusandincreasedseizuresusceptibilitytokainate AT haginoyakazuhiro cux2deficiencycausesfacilitationofexcitatorysynaptictransmissionontohippocampusandincreasedseizuresusceptibilitytokainate AT uematsumitsugu cux2deficiencycausesfacilitationofexcitatorysynaptictransmissionontohippocampusandincreasedseizuresusceptibilitytokainate AT takahashiyukitoshi cux2deficiencycausesfacilitationofexcitatorysynaptictransmissionontohippocampusandincreasedseizuresusceptibilitytokainate AT morimotomasafumi cux2deficiencycausesfacilitationofexcitatorysynaptictransmissionontohippocampusandincreasedseizuresusceptibilitytokainate AT fujimotoshinji cux2deficiencycausesfacilitationofexcitatorysynaptictransmissionontohippocampusandincreasedseizuresusceptibilitytokainate AT osakahitoshi cux2deficiencycausesfacilitationofexcitatorysynaptictransmissionontohippocampusandincreasedseizuresusceptibilitytokainate AT ogunihirokazu cux2deficiencycausesfacilitationofexcitatorysynaptictransmissionontohippocampusandincreasedseizuresusceptibilitytokainate AT osawamakiko cux2deficiencycausesfacilitationofexcitatorysynaptictransmissionontohippocampusandincreasedseizuresusceptibilitytokainate AT ishiiatsushi cux2deficiencycausesfacilitationofexcitatorysynaptictransmissionontohippocampusandincreasedseizuresusceptibilitytokainate AT hiroseshinichi cux2deficiencycausesfacilitationofexcitatorysynaptictransmissionontohippocampusandincreasedseizuresusceptibilitytokainate AT kanekosunao cux2deficiencycausesfacilitationofexcitatorysynaptictransmissionontohippocampusandincreasedseizuresusceptibilitytokainate AT inoueyushi cux2deficiencycausesfacilitationofexcitatorysynaptictransmissionontohippocampusandincreasedseizuresusceptibilitytokainate AT mooreadrianwalton cux2deficiencycausesfacilitationofexcitatorysynaptictransmissionontohippocampusandincreasedseizuresusceptibilitytokainate AT yamakawakazuhiro cux2deficiencycausesfacilitationofexcitatorysynaptictransmissionontohippocampusandincreasedseizuresusceptibilitytokainate |