Decreased cohesin in the brain leads to defective synapse development and anxiety-related behavior.
Decreased cohesin in the brain leads to defective synapse development and anxiety-related behavior.
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DOI：
10.1084/jem.20161517
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发表时间：
2017-05-01
期刊：
影响因子：
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通讯作者：
Yamashita T
中科院分区：
文献类型：
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作者：
Fujita Y;Masuda K;Bando M;Nakato R;Katou Y;Tanaka T;Nakayama M;Takao K;Miyakawa T;Tanaka T;Ago Y;Hashimoto H;Shirahige K;Yamashita T
黏连蛋白与发育障碍科尔内利亚德兰格综合征有关。Fujita等人表明，发育中的大脑中低水平的粘着蛋白表达导致基因表达的变化，这反过来又导致特异性和异常的神经元和行为表型。异常的表观遗传调节可导致神经系统发育异常。在这里，我们试图通过研究蛋白质复合物粘附素来了解这种情况发生的机制，该蛋白质复合物粘附素被认为是调节基因表达的，并且当有缺陷时，与更高水平的脑功能障碍和发育障碍科尔内利亚德兰格综合征（CdLS）相关。我们产生了条件性Smc 3敲除小鼠，并观察到Smc 3 +/−小鼠大脑皮层中更大的树突复杂性和更多的未成熟突触。Smc 3 +/−小鼠也表现出更多的焦虑相关行为，这是CdLS的一种症状。此外，RNA测序后的基因本体分析表明，Smc 3 +/−小鼠中免疫过程的富集，特别是对干扰素的反应。事实上，在他们的皮层神经元中形成的突触更少，这种表型被STAT 1敲低所拯救。因此，发育中的大脑中低水平的粘着蛋白表达导致基因表达的变化，这反过来又导致特定的和异常的神经元和行为表型。
Cohesin is associated with the developmental disorder Cornelia de Lange syndrome. Fujita et al. show that low levels of cohesin expression in the developing brain result in changes in gene expression that in turn lead to a specific and abnormal neuronal and behavioral phenotype. Abnormal epigenetic regulation can cause the nervous system to develop abnormally. Here, we sought to understand the mechanism by which this occurs by investigating the protein complex cohesin, which is considered to regulate gene expression and, when defective, is associated with higher-level brain dysfunction and the developmental disorder Cornelia de Lange syndrome (CdLS). We generated conditional Smc3-knockout mice and observed greater dendritic complexity and larger numbers of immature synapses in the cerebral cortex of Smc3+/− mice. Smc3+/− mice also exhibited more anxiety-related behavior, which is a symptom of CdLS. Further, a gene ontology analysis after RNA-sequencing suggested the enrichment of immune processes, particularly the response to interferons, in the Smc3+/− mice. Indeed, fewer synapses formed in their cortical neurons, and this phenotype was rescued by STAT1 knockdown. Thus, low levels of cohesin expression in the developing brain lead to changes in gene expression that in turn lead to a specific and abnormal neuronal and behavioral phenotype.