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

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。

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.