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LIM 结构域结合蛋白 2（LDB2）与 EGR 在精神分裂症发病机制中的合作。

Cooperation of LIM domain-binding 2 (LDB2) with EGR in the pathogenesis of schizophrenia.

机构信息

Laboratory for Molecular Psychiatry, RIKEN Center for Brain Science, Wako, Japan.

Division of Neuronal Network, Institute of Medical Science, the University of Tokyo, Tokyo, Japan.

出版信息

EMBO Mol Med. 2021 Apr 9;13(4):e12574. doi: 10.15252/emmm.202012574. Epub 2021 Mar 3.

DOI:10.15252/emmm.202012574
PMID:33656268
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8033514/
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.

摘要

基因组缺陷的大效应量有助于阐明精神障碍未知的病理结构。我们之前曾报道过一例精神分裂症患者存在染色体 4 和 13 之间的平衡易位，发现染色体 4 内的断点位于 LDB2 基因附近。我们在此表明，Ldb2 敲除 (KO) 小鼠表现出与精神障碍相关的多种缺陷。特别是，Ldb2 KO 小鼠在恐惧条件反射范式中表现出缺陷。对杏仁核的分析表明，受即时早期基因 Arc 控制的突触活动失调参与了这些表型。我们表明 LDB2 与已知的转录因子形成蛋白复合物。一致地，ChIP-seq 分析表明，LDB2 在人类神经球中结合了 > 10000 个基因组位点。我们发现，其中许多位点，包括 ARC 的启动子区域，被 EGR 转录因子占据。我们之前的研究表明 EGR 家族基因与精神分裂症有关。总的来说，这些发现表明，LDB2-EGR 轴控制的基因表达失调是某些精神障碍发病机制的基础。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/22e6/8033514/8a63108c2186/EMMM-13-e12574-g016.jpg
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