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Tet3 ablation in adult brain neurons increases anxiety-like behavior and regulates cognitive function in mice.
Molecular Psychiatry ( IF 9.6 ) Pub Date : 2020-02-26 , DOI: 10.1038/s41380-020-0695-7
Cláudia Antunes 1, 2 , Jorge D Da Silva 1, 2 , Sónia Guerra-Gomes 1, 2 , Nuno D Alves 1, 2 , Fábio Ferreira 1, 2 , Eduardo Loureiro-Campos 1, 2 , Miguel R Branco 3 , Nuno Sousa 1, 2 , Wolf Reik 4, 5 , Luísa Pinto 1, 2 , C Joana Marques 6, 7
Affiliation  

TET3 is a member of the ten-eleven translocation (TET) family of enzymes which oxidize 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC). Tet3 is highly expressed in the brain, where 5hmC levels are most abundant. In adult mice, we observed that TET3 is present in mature neurons and oligodendrocytes but is absent in astrocytes. To investigate the function of TET3 in adult postmitotic neurons, we crossed Tet3 floxed mice with a neuronal Cre-expressing mouse line, Camk2a-CreERT2, obtaining a Tet3 conditional KO (cKO) mouse line. Ablation of Tet3 in adult mature neurons resulted in increased anxiety-like behavior with concomitant hypercorticalism, and impaired hippocampal-dependent spatial orientation. Transcriptome and gene-specific expression analysis of the hippocampus showed dysregulation of genes involved in glucocorticoid signaling pathway (HPA axis) in the ventral hippocampus, whereas upregulation of immediate early genes was observed in both dorsal and ventral hippocampal areas. In addition, Tet3 cKO mice exhibit increased dendritic spine maturation in the ventral CA1 hippocampal subregion. Based on these observations, we suggest that TET3 is involved in molecular alterations that govern hippocampal-dependent functions. These results reveal a critical role for epigenetic modifications in modulating brain functions, opening new insights into the molecular basis of neurological disorders.

中文翻译:

成年脑神经元中的 Tet3 消融会增加小鼠的焦虑样行为并调节认知功能。

TET3 是 10-11 易位 (TET) 酶家族的成员,可将 5-甲基胞嘧啶 (5mC) 氧化成 5-羟甲基胞嘧啶 (5hmC)。Tet3 在大脑中高度表达,其中 5hmC 水平最为丰富。在成年小鼠中,我们观察到 TET3 存在于成熟神经元和少突胶质细胞中,但在星形胶质细胞中不存在。为了研究 TET3 在成人有丝分裂后神经元中的功能,我们将 Tet3 floxed 小鼠与表达神经元 Cre 的小鼠系 Camk2a-CreERT2 杂交,获得了 Tet3 条件 KO (cKO) 小鼠系。成人成熟神经元中 Tet3 的消融导致焦虑样行为增加,同时伴有皮质亢进,以及海马依赖性空间定向受损。海马的转录组和基因特异性表达分析显示腹侧海马中涉及糖皮质激素信号通路(HPA 轴)的基因失调,而在背侧和腹侧海马区均观察到即刻早期基因的上调。此外,Tet3 cKO 小鼠在腹​​侧 CA1 海马亚区表现出增加的树突棘成熟。基于这些观察,我们认为 TET3 参与了控制海马依赖性功能的分子改变。这些结果揭示了表观遗传修饰在调节大脑功能中的关键作用,为神经系统疾病的分子基础开辟了新的见解。此外,Tet3 cKO 小鼠在腹​​侧 CA1 海马亚区表现出增加的树突棘成熟。基于这些观察,我们认为 TET3 参与了控制海马依赖性功能的分子改变。这些结果揭示了表观遗传修饰在调节大脑功能中的关键作用,为神经系统疾病的分子基础开辟了新的见解。此外,Tet3 cKO 小鼠在腹​​侧 CA1 海马亚区表现出增加的树突棘成熟。基于这些观察,我们认为 TET3 参与了控制海马依赖性功能的分子改变。这些结果揭示了表观遗传修饰在调节大脑功能中的关键作用,为神经系统疾病的分子基础开辟了新的见解。
更新日期:2020-02-26
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