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Human Molecular Genetics Advance Access published online on December 8, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddi033
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Human Molecular Genetics, Vol. 14, No. 3 © Oxford University Press 2005; all rights reserved

Article

The cerebellar transcriptome during postnatal development of the Ts1Cje mouse, a segmental trisomy model for Down syndrome

L. Dauphinot 1, R. Lyle 2, I. Rivals 3, M. Tran Dang 1, R. X. Moldrich 1, G. Golfier 1, L. Ettwiller 1, K. Toyama 4, J. Rossier 1, L. Personnaz 3, S. E. Antonarakis 2, C. J. Epstein 5, P.-M. Sinet 4, and M.-C. Potier 1*

1 Unité Mixte de Recherche 7637 Centre National de la Recherche Scientifique, Ecole Supérieure de Physique et de Chimie Industrielles, 10, rue Vauquelin 75005 Paris France
2 Department of Genetic Medicine and Development, University of Geneva Medical School, 1 rue Michel Servet, 1211 Geneva, Switzerland
3 Equipe de Statistique Appliquée, Ecole Supérieure de Physique et de Chimie Industrielles, 10, rue Vauquelin 75005 Paris France
4 Institut National de la Santé Et de la Recherche Médicale Unité 549, Institut Paul Broca, 2ter, rue d'Alésia 75014 Paris, France
5 Department of Pediatrics, UCSF, San Francisco, CA 94143-0748, USA

* To whom correspondence should be addressed.
M.-C. Potier, E-mail: marie-claude.potier{at}espci.fr


  Abstract

The central nervous system of persons with Down syndrome presents cytoarchitectural abnormalities that likely result from gene dosage effects that affect the expression of key developmental genes. To test this hypothesis, we have investigated the transcriptome of the cerebellum of the Ts1Cje mouse model of Down syndrome during postnatal development using microarrays and quantitative PCR. Genes present in three copies were consistently over expressed, with a mean ratio relative to euploid of 1.52 as determined by quantitative PCR. Out of 63 three-copy genes tested only 5, 9 and 7 had ratios >2 or <1.2 at postnatal days 0 (P0), P15 and P30, respectively. This gene dosage effect was associated with a dysregulation of the expression of some two-copy genes. Out of a total of 8258 genes examined, the Ts1Cje/euploid ratios differed significantly from 1.0 for 406 (80 and 154 with ratios >1.5 and <0.7, respectively), 333 (11>1.5 and 55<0.7) and 246 (59>1.5 and 69<0.7) at P0, P15 and P30 respectively. Among the two-copy genes differentially expressed in the trisomic cerebellum, 6 homeobox genes, 2 belonging to the Notch pathway, were severely repressed. Overall, at P0, transcripts involved in cell differentiation and development were over represented among the dysregulated genes, suggesting that cell differentiation and migration might be altered more than cell proliferation. Finally, global gene profiling revealed that transcription in Ts1Cje mice is more affected by developmental changes than by the trisomic state and that there is no apparent detectable delay in the postnatal development of the cerebellum of Ts1Cje mice.


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