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

一种染色质重塑蛋白的突变，ATRX会导致阿尔法-地中海贫血X连锁智力低下综合征。我们产生了缺失外显子2的ATRX突变小鼠(ATRXdE2小鼠)。在情景恐惧条件反射测试中，ATRXdE2小鼠的总冰冻时间减少了。ATRXdE2小鼠表现出由高频刺激引起的海马区CA1区长时程增强(LTP)显著降低。ATRXdE2小鼠在内侧前额叶皮质表现出异常的树突棘形成。我们证实了CaMKII，PAKS的磷酸化增加和蛋白磷酸酶I的活性降低。接下来，我们有条件地灭活了小鼠的ATRX同源物。靶向缺失外显子6的策略。将pGK-neo选择盒插入内含子6，Cre重组酶的lox P靶点位于内含子7。建立了Cre介导的ES细胞全长atrx蛋白的消融方法，并建立了嵌合体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.