TY - JOUR
T1 - Cooperation of LIM domain-binding 2 (LDB2) with EGR in the pathogenesis of schizophrenia
AU - Ohnishi, Tetsuo
AU - Kiyama, Yuji
AU - Arima-Yoshida, Fumiko
AU - Kadota, Mitsutaka
AU - Ichikawa, Tomoe
AU - Yamada, Kazuyuki
AU - Watanabe, Akiko
AU - Ohba, Hisako
AU - Tanaka, Kaori
AU - Nakaya, Akihiro
AU - Horiuchi, Yasue
AU - Iwayama, Yoshimi
AU - Toyoshima, Manabu
AU - Ogawa, Itone
AU - Shimamoto-Mitsuyama, Chie
AU - Maekawa, Motoko
AU - Balan, Shabeesh
AU - Arai, Makoto
AU - Miyashita, Mitsuhiro
AU - Toriumi, Kazuya
AU - Nozaki, Yayoi
AU - Kurokawa, Rumi
AU - Suzuki, Kazuhiro
AU - Yoshikawa, Akane
AU - Toyota, Tomoko
AU - Hosoya, Toshihiko
AU - Okuno, Hiroyuki
AU - Bito, Haruhiko
AU - Itokawa, Masanari
AU - Kuraku, Shigehiro
AU - Manabe, Toshiya
AU - Yoshikawa, Takeo
N1 - Funding Information:
We thank Dr. T. Kato (RIKEN CBS) for kindly offering us unpublished information on the variant in the bipolar patient, Drs. T. Kimura (National Center for Geriatrics and Gerontology, Japan) and H. Furudate (Saitama University) for useful suggestions, and Ms. C. Kimura for technical support. We are also grateful to Lexicon Pharmaceuticals and the MMRRC for providing us with a sperm stock of KO mouse. We are deeply thankful to the members of the Research Resources Division of RIKEN CBS for their technical support on peptide synthesis, production of polyclonal antibodies in rabbits, DNA‐sequencing service, animal care, and mouse embryo manipulation, and to the members of the Laboratory for Phyloinformatics, RIKEN BDR for the NGS sequencing. This research was supported by JSPS KAKENHI under Grant Numbers 16K07017, 24591737, 21591535, and 20K07934 (to T. O.), 15K01848 (to Y. K.), 17790834 (to M. A.), and 23220008, 25116505, 19H03321 and 19H04876 (to T. M.), and by the Grant‐in‐Aid for Scientific Research on Innovative Areas from the MEXT under Grant Numbers JP18H05435 (to T. Y.). The funding agencies had no influence on study design, data collection, data analysis, interpretation, or writing of the report. RLIM Ldb2
Funding Information:
We thank Dr. T. Kato (RIKEN CBS) for kindly offering us unpublished information on the RLIM variant in the bipolar patient, Drs. T. Kimura (National Center for Geriatrics and Gerontology, Japan) and H. Furudate (Saitama University) for useful suggestions, and Ms. C. Kimura for technical support. We are also grateful to Lexicon Pharmaceuticals and the MMRRC for providing us with a sperm stock of Ldb2 KO mouse. We are deeply thankful to the members of the Research Resources Division of RIKEN CBS for their technical support on peptide synthesis, production of polyclonal antibodies in rabbits, DNA-sequencing service, animal care, and mouse embryo manipulation, and to the members of the Laboratory for Phyloinformatics, RIKEN BDR for the NGS sequencing. This research was supported by JSPS KAKENHI under Grant Numbers 16K07017, 24591737, 21591535, and 20K07934 (to T. O.), 15K01848 (to Y. K.), 17790834 (to M. A.), and 23220008, 25116505, 19H03321 and 19H04876 (to T. M.), and by the Grant-in-Aid for Scientific Research on Innovative Areas from the MEXT under Grant Numbers JP18H05435 (to T. Y.). The funding agencies had no influence on study design, data collection, data analysis, interpretation, or writing of the report.
Publisher Copyright:
© 2021 The Authors. Published under the terms of the CC BY 4.0 license
PY - 2021/4/9
Y1 - 2021/4/9
N2 - 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.
AB - 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.
KW - ChIP-seq
KW - amygdala
KW - balanced chromosomal translocation
KW - behavior
KW - knockout mouse
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U2 - 10.15252/emmm.202012574
DO - 10.15252/emmm.202012574
M3 - Article
C2 - 33656268
AN - SCOPUS:85101928825
SN - 1757-4676
VL - 13
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
IS - 4
M1 - e12574
ER -