Molecular pathological mechanisms of the brain development disorder using the chromatin-remodeling molecule ATRX gene knockout mouse

染色质重塑分子ATRX基因敲除小鼠脑发育障碍的分子病理机制

• 批准号: 23300147
• 负责人: KITAJIMA Isao
• 金额: $ 9.4万
• 依托单位: University of Toyama
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2011
• 资助国家: 日本
• 起止时间: 2011-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-23300147/
• 关键词: 脳発達障害; エピジェネテイクス; クロマチンリモデリング; ノックアウトマウス; スパイン; 神経科学; 脳神経疾患; 応用動物; 精神遅滞; ＡＴＲ-Ｘ症候群; コンデショナルノックアウトマウス; ＥＳ細胞; 精神運動発達障害; クロマチンロモデリング; ATRX症候群; ES細胞; 発達障害

Mutation in a chromatin remodeling protein, ATRX causes alfa-thalassemia X-linked mental retardation syndrome. We generated ATRX mutant mice lacking exon2 (ATRXdE2 mice). In a contextual fear conditioning test, total freezing time was decreased in ATRXdE2 mice. ATRXdE2 mice showed significantly reduced long-term potentiation (LTP) in the hippocampal CA1 region evoked by high-frequency stimulation. ATRXdE2 mice exhibited abnormal dendritic spine formation in the medial prefrontal cortex. We confirmed that increased phosphorylation of CaMKII,PAKs and reduced activity of protein phosphatase I. Next, we conditionally inactivated the homolog in mice, Atrx. Strategy for targeted deletion of exon 6. The PGK-neo selection cassette was inserted in intron 6 and the lox P target sites of the Cre recombinase were in intron 7. Cre-mediated ablation of full-length atrx protein in ES cells were established and then chimera ATRX loxp mice were developed.

ATRX是一种染色质重塑蛋白的突变，可导致α-地中海贫血X连锁精神发育迟滞综合征。我们产生了缺乏外显子2的ATRX突变小鼠（ATRXdE 2小鼠）。在情境恐惧条件反射测试中，ATRXdE 2小鼠的总冻结时间减少。ATRXdE 2小鼠显示 显著降低高频刺激诱发的海马CA 1区长时程增强（LTP）。ATRXdE 2小鼠在内侧前额叶皮质中表现出异常的树突棘形成。 我们证实，增加磷酸化的CaMK Ⅱ，PAKs和降低活性的蛋白磷酸酶I。 接下来，我们在小鼠中有条件地灭活了同源物Atrx。第6号外显子靶向缺失策略。 PGK-neo选择盒插入内含子6中，Cre重组酶的loxP靶位点位于内含子7中。建立Cre介导的ES细胞中全长atrx蛋白的去除，然后开发嵌合体ATRX loxp小鼠。

项目成果

Physical and Functional Interaction of the Active Zone Protein CAST/ERC2 and the -subunit of the Voltage-dependent Ca2+ Channel.

活性区蛋白 CAST/ERC2 和

• 发表时间: 2012
• 期刊: J. Biochem.
• 作者: Kiyonaka;S.
• 通讯作者: S.

The Novel Cognitive Enhancer ST101 Enhances Acetylcholine Release in Mouse Dorsal Hippocampus Through T-type Voltage-Gated Calcium Channel Stimulation.

新型认知增强剂 ST101 通过 T 型电压门控钙通道刺激增强小鼠背海马的乙酰胆碱释放。

• 发表时间: 2013
• 期刊: J Pharmacol Sci.
• 作者: Yamamoto Y;Shioda N;Han F;Moriguchi S;Fukunaga K.
• 通讯作者: Fukunaga K.

Novel Dopamine D2 Receptor Signaling through Proteins Interacting with the Third Cytoplasmic Loop

• DOI: 10.1007/s12035-011-8227-8
• 发表时间: 2012-02-01
• 期刊: MOLECULAR NEUROBIOLOGY
• 影响因子: 5.1
• 作者: Fukunaga, Kohji;Shioda, Norifumi
• 通讯作者: Shioda, Norifumi

Reduced Expression of the ATRX Gene, a Chromatin-Remodeling Factor, Causes Hippocampal Dysfunction in Mice

• DOI: 10.1002/hipo.20782
• 发表时间: 2011-06-01
• 期刊: HIPPOCAMPUS
• 影响因子: 3.5
• 作者: Nogami, Tatsuya;Beppu, Hideyuki;Kitajima, Isao
• 通讯作者: Kitajima, Isao

NF-kB activity in the peripheral blood lymphocytes correlates with metabolic syndrome-related biomarkers in patients with essential hypertension.

原发性高血压患者外周血淋巴细胞中的 NF-kB 活性与代谢综合征相关生物标志物相关。

• 发表时间: 2011
• 作者: Kitajima I;Harada K; Tomoda F;Kagitani S;Koike TInoue H
• 通讯作者: Koike TInoue H