Mice containing a human chromosome 21 model behavioral impairment and cardiac anomalies of Down's syndrome

Trisomy 21 (Ts21) is the most common live-born human aneuploidy; it results in a constellation of features known as Down's syndrome (DS), Ts21 is the most frequent cause of congenital heart defects and the leading genetic cau se of mental retardation. To investigate the gene dosage effects of an extr a copy of human chromosome 21 (Chr 21) on various phenotypes, we used micro cell-mediated chromosome transfer to create embryonic stem (ES) cells conta ining Chr 21, ES cell lines retaining Chr 21 as an independent chromosome w ere used to produce chimeric mice with a substantial contribution from Chr 21-containing cells. Fluorescence in situ hybridization and PCR-based DNA a nalysis revealed that Chr 21 was substationally intact but had sustained a small deletion. The freely segregating Chr 21 was lost during development i n some tissues, resulting in a panel of chimeric mice with various mosaicis m as regards retention of the Chr 21, These chimeric mice showed a high cor relation between retention of Chr 21 in the brain and impairment in learnin g or emotional behavior by open-field, contextual fear conditioning and for ced swim tests. Hypoplastic thymus and cardiac defects, i.e. double outlet right ventricle and riding aorta, were observed in a considerable number of chimeric mouse fetuses with a high contribution of Chr 21. These chimeric mice mimic a wide variety of phenotypic traits of DS, revealing the utility of mice containing Chr 21 as unique models for DS and for the identificati on of genes responsible for DS.