EMBO Molecular Medicine (Apr 2021)
Cooperation of LIM domain‐binding 2 (LDB2) with EGR in the pathogenesis of schizophrenia
- 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
Affiliations
- Tetsuo Ohnishi
- Laboratory for Molecular Psychiatry RIKEN Center for Brain Science Wako Japan
- Yuji Kiyama
- Division of Neuronal Network Institute of Medical Science the University of Tokyo Tokyo Japan
- Fumiko Arima‐Yoshida
- Division of Neuronal Network Institute of Medical Science the University of Tokyo Tokyo Japan
- Mitsutaka Kadota
- Laboratory for Phyloinformatics RIKEN Center for Biosystems Dynamics Research Kobe Japan
- Tomoe Ichikawa
- Schizophrenia Research Project Tokyo Metropolitan Institute of Medical Sciences Shizuoka Japan
- Kazuyuki Yamada
- School of Management Shizuoka Sangyo University Iwata Japan
- Akiko Watanabe
- Laboratory for Molecular Psychiatry RIKEN Center for Brain Science Wako Japan
- Hisako Ohba
- Laboratory for Molecular Psychiatry RIKEN Center for Brain Science Wako Japan
- Kaori Tanaka
- Laboratory for Phyloinformatics RIKEN Center for Biosystems Dynamics Research Kobe Japan
- Akihiro Nakaya
- Laboratory for Molecular Psychiatry RIKEN Center for Brain Science Wako Japan
- Yasue Horiuchi
- Schizophrenia Research Project Tokyo Metropolitan Institute of Medical Sciences Shizuoka Japan
- Yoshimi Iwayama
- Laboratory for Molecular Psychiatry RIKEN Center for Brain Science Wako Japan
- Manabu Toyoshima
- Laboratory for Molecular Psychiatry RIKEN Center for Brain Science Wako Japan
- Itone Ogawa
- Division of Neuronal Network Institute of Medical Science the University of Tokyo Tokyo Japan
- Chie Shimamoto‐Mitsuyama
- Laboratory for Molecular Psychiatry RIKEN Center for Brain Science Wako Japan
- Motoko Maekawa
- Laboratory for Molecular Psychiatry RIKEN Center for Brain Science Wako Japan
- Shabeesh Balan
- Laboratory for Molecular Psychiatry RIKEN Center for Brain Science Wako Japan
- Makoto Arai
- Schizophrenia Research Project Tokyo Metropolitan Institute of Medical Sciences Shizuoka Japan
- Mitsuhiro Miyashita
- Schizophrenia Research Project Tokyo Metropolitan Institute of Medical Sciences Shizuoka Japan
- Kazuya Toriumi
- Schizophrenia Research Project Tokyo Metropolitan Institute of Medical Sciences Shizuoka Japan
- Yayoi Nozaki
- Laboratory for Molecular Psychiatry RIKEN Center for Brain Science Wako Japan
- Rumi Kurokawa
- RIKEN Wako Japan
- Kazuhiro Suzuki
- Schizophrenia Research Project Tokyo Metropolitan Institute of Medical Sciences Shizuoka Japan
- Akane Yoshikawa
- Schizophrenia Research Project Tokyo Metropolitan Institute of Medical Sciences Shizuoka Japan
- Tomoko Toyota
- Laboratory for Molecular Psychiatry RIKEN Center for Brain Science Wako Japan
- Toshihiko Hosoya
- RIKEN Wako Japan
- Hiroyuki Okuno
- Laboratory of Biochemistry and Molecular Biology Graduate School of Medical and Dental Sciences Kagoshima University Kagoshima Japan
- Haruhiko Bito
- Department of Neurochemistry the University of TokyoGraduate School of Medicine Tokyo Japan
- Masanari Itokawa
- Schizophrenia Research Project Tokyo Metropolitan Institute of Medical Sciences Shizuoka Japan
- Shigehiro Kuraku
- Laboratory for Phyloinformatics RIKEN Center for Biosystems Dynamics Research Kobe Japan
- Toshiya Manabe
- Division of Neuronal Network Institute of Medical Science the University of Tokyo Tokyo Japan
- Takeo Yoshikawa
- Laboratory for Molecular Psychiatry RIKEN Center for Brain Science Wako Japan
- DOI
- https://doi.org/10.15252/emmm.202012574
- Journal volume & issue
-
Vol. 13,
no. 4
pp. n/a – n/a
Abstract
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.
Keywords