Global disruption of the cerebellar transcriptome in a Down syndrome mouse model.
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.
Saran
Nidhi G
NG
Department of Physiology, Johns Hopkins School of Medicine, Baltimore, MD 21210, USA.
Pletcher
Mathew T
MT
Natale
JoAnne E
JE
Cheng
Ying
Y
Reeves
Roger H
RH
D000818:Animals; D002531:Cerebellum / Q000166:cytology / Q000378:metabolism*; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000235:genetics*; D015870:Gene Expression; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D012313:RNA / Q000032:analysis; D014158:Transcription, Genetic
D012313:RNA