Research article

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

Julien Laffaire^1,8 , Isabelle Rivals² , Luce Dauphinot^1,8 , Fabien Pasteau¹ , Rosine Wehrle^3,4 , Benoit Larrat⁵ , Tania Vitalis¹ , Randal X Moldrich^1,6 , Jean Rossier¹ , Ralph Sinkus⁵ , Yann Herault⁷ , Isabelle Dusart^3,4 and Marie-Claude Potier^1,8

¹  Laboratoire de Neurobiologie, CNRS UMR7637, ESPCI, Paris, France

²  Equipe de Statistique Appliquee – ESPCI, Paris, France

³  Neurobiologie des Processus Adaptatifs, CNRS UMR7102, Paris, France

⁴  UPMC, Paris, France

⁵  Laboratoire Ondes et Accoustique, UMR7587, ESPCI, Paris, France

⁶  The Queensland Brain Institute, St Lucia, Australia

⁷  IEM, CNRS UMR6218, Orleans, France

⁸  CRICM, CNRS UMR7225, INSERM UMR975, UPMC, CHU Pitie-Salpetriere, Paris, France

author email corresponding author email

BMC Genomics 2009, 10:138doi:10.1186/1471-2164-10-138

Published:	30 March 2009

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.