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

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.