Cooperation of LIM domain‐binding 2 (LDB2) with EGR in the pathogenesis of schizophrenia
Abstract Genomic defects with large effect size can help elucidate unknown pathologic architecture of mental disorders. We previously reported on a patient with schizophrenia and a balanced translocation between chromosomes 4 and 13 and found that the breakpoint within chromosome 4 is located near t...
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Springer Nature
2021-03-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.202012574 |
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| author | Tetsuo Ohnishi Yuji Kiyama Fumiko Arima‐Yoshida Mitsutaka Kadota Tomoe Ichikawa Kazuyuki Yamada Akiko Watanabe Hisako Ohba Kaori Tanaka Akihiro Nakaya Yasue Horiuchi Yoshimi Iwayama Manabu Toyoshima Itone Ogawa Chie Shimamoto‐Mitsuyama Motoko Maekawa Shabeesh Balan Makoto Arai Mitsuhiro Miyashita Kazuya Toriumi Yayoi Nozaki Rumi Kurokawa Kazuhiro Suzuki Akane Yoshikawa Tomoko Toyota Toshihiko Hosoya Hiroyuki Okuno Haruhiko Bito Masanari Itokawa Shigehiro Kuraku Toshiya Manabe Takeo Yoshikawa |
| author_facet | Tetsuo Ohnishi Yuji Kiyama Fumiko Arima‐Yoshida Mitsutaka Kadota Tomoe Ichikawa Kazuyuki Yamada Akiko Watanabe Hisako Ohba Kaori Tanaka Akihiro Nakaya Yasue Horiuchi Yoshimi Iwayama Manabu Toyoshima Itone Ogawa Chie Shimamoto‐Mitsuyama Motoko Maekawa Shabeesh Balan Makoto Arai Mitsuhiro Miyashita Kazuya Toriumi Yayoi Nozaki Rumi Kurokawa Kazuhiro Suzuki Akane Yoshikawa Tomoko Toyota Toshihiko Hosoya Hiroyuki Okuno Haruhiko Bito Masanari Itokawa Shigehiro Kuraku Toshiya Manabe Takeo Yoshikawa |
| author_sort | Tetsuo Ohnishi |
| collection | DOAJ |
| description | Abstract Genomic defects with large effect size can help elucidate unknown pathologic architecture of mental disorders. We previously reported on a patient with schizophrenia and a balanced translocation between chromosomes 4 and 13 and found that the breakpoint within chromosome 4 is located near the LDB2 gene. We show here that Ldb2 knockout (KO) mice displayed multiple deficits relevant to mental disorders. In particular, Ldb2 KO mice exhibited deficits in the fear‐conditioning paradigm. Analysis of the amygdala suggested that dysregulation of synaptic activities controlled by the immediate early gene Arc is involved in the phenotypes. We show that LDB2 forms protein complexes with known transcription factors. Consistently, ChIP‐seq analyses indicated that LDB2 binds to > 10,000 genomic sites in human neurospheres. We found that many of those sites, including the promoter region of ARC, are occupied by EGR transcription factors. Our previous study showed an association of the EGR family genes with schizophrenia. Collectively, the findings suggest that dysregulation in the gene expression controlled by the LDB2‐EGR axis underlies a pathogenesis of subset of mental disorders. |
| format | Article |
| id | doaj-art-c3d643b8363c4222821faa0e5c5dffd8 |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2021-03-01 |
| publisher | Springer Nature |
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| series | EMBO Molecular Medicine |
| spelling | doaj-art-c3d643b8363c4222821faa0e5c5dffd82025-08-20T03:42:52ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842021-03-0113412110.15252/emmm.202012574Cooperation of LIM domain‐binding 2 (LDB2) with EGR in the pathogenesis of schizophreniaTetsuo Ohnishi0Yuji Kiyama1Fumiko Arima‐Yoshida2Mitsutaka Kadota3Tomoe Ichikawa4Kazuyuki Yamada5Akiko Watanabe6Hisako Ohba7Kaori Tanaka8Akihiro Nakaya9Yasue Horiuchi10Yoshimi Iwayama11Manabu Toyoshima12Itone Ogawa13Chie Shimamoto‐Mitsuyama14Motoko Maekawa15Shabeesh Balan16Makoto Arai17Mitsuhiro Miyashita18Kazuya Toriumi19Yayoi Nozaki20Rumi Kurokawa21Kazuhiro Suzuki22Akane Yoshikawa23Tomoko Toyota24Toshihiko Hosoya25Hiroyuki Okuno26Haruhiko Bito27Masanari Itokawa28Shigehiro Kuraku29Toshiya Manabe30Takeo Yoshikawa31Laboratory for Molecular Psychiatry, RIKEN Center for Brain ScienceDivision of Neuronal Network, Institute of Medical Science, the University of TokyoDivision of Neuronal Network, Institute of Medical Science, the University of TokyoLaboratory for Phyloinformatics, RIKEN Center for Biosystems Dynamics ResearchSchizophrenia Research Project, Tokyo Metropolitan Institute of Medical SciencesSchool of Management, Shizuoka Sangyo UniversityLaboratory for Molecular Psychiatry, RIKEN Center for Brain ScienceLaboratory for Molecular Psychiatry, RIKEN Center for Brain ScienceLaboratory for Phyloinformatics, RIKEN Center for Biosystems Dynamics ResearchLaboratory for Molecular Psychiatry, RIKEN Center for Brain ScienceSchizophrenia Research Project, Tokyo Metropolitan Institute of Medical SciencesLaboratory for Molecular Psychiatry, RIKEN Center for Brain ScienceLaboratory for Molecular Psychiatry, RIKEN Center for Brain ScienceDivision of Neuronal Network, Institute of Medical Science, the University of TokyoLaboratory for Molecular Psychiatry, RIKEN Center for Brain ScienceLaboratory for Molecular Psychiatry, RIKEN Center for Brain ScienceLaboratory for Molecular Psychiatry, RIKEN Center for Brain ScienceSchizophrenia Research Project, Tokyo Metropolitan Institute of Medical SciencesSchizophrenia Research Project, Tokyo Metropolitan Institute of Medical SciencesSchizophrenia Research Project, Tokyo Metropolitan Institute of Medical SciencesLaboratory for Molecular Psychiatry, RIKEN Center for Brain ScienceRIKENSchizophrenia Research Project, Tokyo Metropolitan Institute of Medical SciencesSchizophrenia Research Project, Tokyo Metropolitan Institute of Medical SciencesLaboratory for Molecular Psychiatry, RIKEN Center for Brain ScienceRIKENLaboratory of Biochemistry and Molecular Biology, Graduate School of Medical and Dental Sciences, Kagoshima UniversityDepartment of Neurochemistry, the University of Tokyo, Graduate School of MedicineSchizophrenia Research Project, Tokyo Metropolitan Institute of Medical SciencesLaboratory for Phyloinformatics, RIKEN Center for Biosystems Dynamics ResearchDivision of Neuronal Network, Institute of Medical Science, the University of TokyoLaboratory for Molecular Psychiatry, RIKEN Center for Brain ScienceAbstract Genomic defects with large effect size can help elucidate unknown pathologic architecture of mental disorders. We previously reported on a patient with schizophrenia and a balanced translocation between chromosomes 4 and 13 and found that the breakpoint within chromosome 4 is located near the LDB2 gene. We show here that Ldb2 knockout (KO) mice displayed multiple deficits relevant to mental disorders. In particular, Ldb2 KO mice exhibited deficits in the fear‐conditioning paradigm. Analysis of the amygdala suggested that dysregulation of synaptic activities controlled by the immediate early gene Arc is involved in the phenotypes. We show that LDB2 forms protein complexes with known transcription factors. Consistently, ChIP‐seq analyses indicated that LDB2 binds to > 10,000 genomic sites in human neurospheres. We found that many of those sites, including the promoter region of ARC, are occupied by EGR transcription factors. Our previous study showed an association of the EGR family genes with schizophrenia. Collectively, the findings suggest that dysregulation in the gene expression controlled by the LDB2‐EGR axis underlies a pathogenesis of subset of mental disorders.https://doi.org/10.15252/emmm.202012574amygdalabalanced chromosomal translocationbehaviorChIP‐seqknockout mouse |
| spellingShingle | Tetsuo Ohnishi Yuji Kiyama Fumiko Arima‐Yoshida Mitsutaka Kadota Tomoe Ichikawa Kazuyuki Yamada Akiko Watanabe Hisako Ohba Kaori Tanaka Akihiro Nakaya Yasue Horiuchi Yoshimi Iwayama Manabu Toyoshima Itone Ogawa Chie Shimamoto‐Mitsuyama Motoko Maekawa Shabeesh Balan Makoto Arai Mitsuhiro Miyashita Kazuya Toriumi Yayoi Nozaki Rumi Kurokawa Kazuhiro Suzuki Akane Yoshikawa Tomoko Toyota Toshihiko Hosoya Hiroyuki Okuno Haruhiko Bito Masanari Itokawa Shigehiro Kuraku Toshiya Manabe Takeo Yoshikawa Cooperation of LIM domain‐binding 2 (LDB2) with EGR in the pathogenesis of schizophrenia EMBO Molecular Medicine amygdala balanced chromosomal translocation behavior ChIP‐seq knockout mouse |
| title | Cooperation of LIM domain‐binding 2 (LDB2) with EGR in the pathogenesis of schizophrenia |
| title_full | Cooperation of LIM domain‐binding 2 (LDB2) with EGR in the pathogenesis of schizophrenia |
| title_fullStr | Cooperation of LIM domain‐binding 2 (LDB2) with EGR in the pathogenesis of schizophrenia |
| title_full_unstemmed | Cooperation of LIM domain‐binding 2 (LDB2) with EGR in the pathogenesis of schizophrenia |
| title_short | Cooperation of LIM domain‐binding 2 (LDB2) with EGR in the pathogenesis of schizophrenia |
| title_sort | cooperation of lim domain binding 2 ldb2 with egr in the pathogenesis of schizophrenia |
| topic | amygdala balanced chromosomal translocation behavior ChIP‐seq knockout mouse |
| url | https://doi.org/10.15252/emmm.202012574 |
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