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Human Molecular Genetics Advance Access originally published online on July 1, 2003
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Human Molecular Genetics, 2003, Vol. 12, No. 16 2013-2019
DOI: 10.1093/hmg/ddg217
© 2003 Oxford University Press

Global disruption of the cerebellar transcriptome in a Down syndrome mouse model

Nidhi G. Saran1, Mathew T. Pletcher1,{dagger}, JoAnne E. Natale2, Ying Cheng2 and Roger H. Reeves1,*

1Department of Physiology, Johns Hopkins School of Medicine, Baltimore, MD 21210, USA and 2Research Centers for Genetic Medicine and Neuroscience, Children's National Medical Center, 111 Michigan Avenue, NW, Washington, DC 20010, USA

Received April 16, 2003; Revised June 13, 2003; Accepted June 23, 2003

Trisomy 21 (Down syndrome) results in cerebellar dysmorphology with direct parallels in the Ts65Dn mouse. Despite pronounced changes in morphology, cerebellar function is not markedly different. As a first test of whether those cerebellar cells that have survived to adulthood in trisomic mice are equivalent to euploid cells, we used microarrays to assess the trisomic and euploid cerebella. Trisomic and euploid transcriptomes were robustly distinguished. Changes in expression of individual genes were very subtle, but the differences in respective transcriptome phenotypes extended deeply into the set of nearly 7000 probes (genes) located throughout the genome. In contrast to deterministic models of gene action in trisomy, examination of the discriminating genes in two independent experiments suggests that the global perturbation includes a significant stochastic component. Thus, dosage imbalance of 124 genes in Ts65Dn mice alters the expression of thousands of genes to create a variable trisomic transcriptome. This global destabilization has important implications for approaches to ameliorative therapies in Down syndrome.

* To whom correspondence should be addressed. Tel: +1 4109556621; Fax: +1 4106148731; Email: rreeves{at}jhmi.edu

{dagger} Present address: The Scripps Research Institute, Department of Cell Biology, ICND-216, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA.


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