Gene expression signature of cerebellar hypoplasia in a mouse model of Down syndrome during postnatal development

Laffaire, Julien, Rivals, Isabelle, Dauphinot, Luce, Pasteau, Fabien, Wehrle, Rosine, Larrat, Benoit, Vitalis, Tania, Moldrich, Randal X., Rossier, Jean, Sinkus, Ralph, Herault, Yann, Dusart, Isabelle and Potier, Marie-Claude (2009) Gene expression signature of cerebellar hypoplasia in a mouse model of Down syndrome during postnatal development. BMC Genomics, 10 9: 138.1-138.15. doi:10.1186/1471-2164-10-138

Author Laffaire, Julien
Rivals, Isabelle
Dauphinot, Luce
Pasteau, Fabien
Wehrle, Rosine
Larrat, Benoit
Vitalis, Tania
Moldrich, Randal X.
Rossier, Jean
Sinkus, Ralph
Herault, Yann
Dusart, Isabelle
Potier, Marie-Claude
Title Gene expression signature of cerebellar hypoplasia in a mouse model of Down syndrome during postnatal development
Journal name BMC Genomics   Check publisher's open access policy
ISSN 1471-2164
Publication date 2009-03-30
Year available 2009
Sub-type Article (original research)
DOI 10.1186/1471-2164-10-138
Open Access Status DOI
Volume 10
Issue 9
Start page 138.1
End page 138.15
Total pages 15
Editor Norton, Melissa
Place of publication United Kingdom
Publisher Biomed Central
Language eng
Subject C1
730104 Nervous system and disorders
110903 Central Nervous System
060405 Gene Expression (incl. Microarray and other genome-wide approaches)
Abstract Background Down syndrome is a chromosomal disorder caused by the presence of three copies of chromosome 21. The mechanisms by which this aneuploidy produces the complex and variable phenotype observed in people with Down syndrome are still under discussion. Recent studies have demonstrated an increased transcript level of the three-copy genes with some dosage compensation or amplification for a subset of them. The impact of this gene dosage effect on the whole transcriptome is still debated and longitudinal studies assessing the variability among samples, tissues and developmental stages are needed. Results We thus designed a large scale gene expression study in mice (the Ts1Cje Down syndrome mouse model) in which we could measure the effects of trisomy 21 on a large number of samples (74 in total) in a tissue that is affected in Down syndrome (the cerebellum) and where we could quantify the defect during postnatal development in order to correlate gene expression changes to the phenotype observed. Statistical analysis of microarray data revealed a major gene dosage effect: for the three-copy genes as well as for a 2 Mb segment from mouse chromosome 12 that we show for the first time as being deleted in the Ts1Cje mice. This gene dosage effect impacts moderately on the expression of euploid genes (2.4 to 7.5% differentially expressed). Only 13 genes were significantly dysregulated in Ts1Cje mice at all four postnatal development stages studied from birth to 10 days after birth, and among them are 6 three-copy genes. The decrease in granule cell proliferation demonstrated in newborn Ts1Cje cerebellum was correlated with a major gene dosage effect on the transcriptome in dissected cerebellar external granule cell layer. Conclusion High throughput gene expression analysis in the cerebellum of a large number of samples of Ts1Cje and euploid mice has revealed a prevailing gene dosage effect on triplicated genes. Moreover using an enriched cell population that is thought responsible for the cerebellar hypoplasia in Down syndrome, a global destabilization of gene expression was not detected. Altogether these results strongly suggest that the three-copy genes are directly responsible for the phenotype present in cerebellum. We provide here a short list of candidate genes.
Keyword Biotechnology & Applied Microbiology
Genetics & Heredity
Biotechnology & Applied Microbiology
Genetics & Heredity
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID 15-14-30000
Institutional Status Non-UQ
Additional Notes Article number 138

Document type: Journal Article
Sub-type: Article (original research)
Collections: 2010 Higher Education Research Data Collection
Queensland Brain Institute Publications
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Citation counts: TR Web of Science Citation Count  Cited 31 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 35 times in Scopus Article | Citations
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Created: Fri, 08 May 2009, 19:39:27 EST by Debra McMurtrie on behalf of Queensland Brain Institute