Human Molecular Genetics, 2001, Vol. 10, No. 11 1163-1175
© 2001 Oxford University Press
Mice containing a human chromosome 21 model behavioral impairment and cardiac anomalies of Down’s syndrome
1Department of Molecular and Cell Genetics, School of Life Sciences, Faculty of Medicine, Tottori University and CREST (JST), Nishimachi 86, Yonago, Tottori 683-8503, Japan, 2Pharmaceutical Research Laboratory, KIRIN Brewery Co. Ltd, Miyahara-cho 3, Takasaki, Gunma 370-1295, Japan, 3Department of Pathology, Saga Medical School, Nabeshima 5, Saga 849-8501, Japan, 4First Department of Anatomy, Faculty of Medicine, Tottori University, Nishimachi 86, Yonago, Tottori 683-8503, Japan, 5Mitsubishi Kasei Institute of Life Sciences, Minamiooya 11, Machida, Tokyo 194-8511, Japan and 6Department of Physiology, Johns Hopkins University School of Medicine, 725 North Wolf Street, Baltimore, MD 21205, USA
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 cause of mental retardation. To investigate the gene dosage effects of an extra copy of human chromosome 21 (Chr 21) on various phenotypes, we used microcell-mediated chromosome transfer to create embryonic stem (ES) cells containing Chr 21. ES cell lines retaining Chr 21 as an independent chromosome were used to produce chimeric mice with a substantial contribution from Chr 21-containing cells. Fluorescence in situ hybridization and PCR-based DNA analysis revealed that Chr 21 was substationally intact but had sustained a small deletion. The freely segregating Chr 21 was lost during development in some tissues, resulting in a panel of chimeric mice with various mosaicism as regards retention of the Chr 21. These chimeric mice showed a high correlation between retention of Chr 21 in the brain and impairment in learning or emotional behavior by open-field, contextual fear conditioning and forced 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 identification of genes responsible for DS.
+ To whom correspondence should be addressed. Tel: +81 859 34 8260; Fax: +81 859 34 8134; Email: oshimura@grape.med.tottori-u.ac.jp
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