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
EMBO molecular medicine 2021 Apr 09Genomic 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. © 2021 The Authors. Published under the terms of the CC BY 4.0 license.
Citation
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. 2021 Apr 09;13(4):e12574
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PMID: 33656268
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