Nd expressed in the external granule cell layer is more likely to affect neuron maturation than proliferation. However it is unlikely that the cerebellum phenotype observed in Ts1Cje mice results from the Mmu12 deletion since a very similar phenotype is present in the Ts65Dn PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/28541393 mouse model that do not show any PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/26820258 rearrangement on Mmu12. We found a decrease in FG 7142 Cdca7l gene expression, a transcription factor involved in cell apoptosis [41] and medulloblastoma transformation [41]. Since Cdca7l is located approximately 200 kb proximal to the translocation breakpoint on MMU12 (Figure 6) we concluded that the gene dosage effect extends to regions that are close to the chromosomal rearrangement. We then looked for genes that were regulated during normal postnatal development of the cerebellum and that were also differentially expressed between Ts1Cje and euploid cerebellum at one of the postnatal stages tested. Among the 1187 genes found, only three were triplicated: Olig1, Dscam and Girk2. Olig1 encodes a basic helix-loophelix transcription factor that is expressed in both the developing and mature vertebrate central nervous system.Page 8 of(page number not for citation purposes)Figure 4 tion Mean gene expression ratio according to chromosomal locaMean gene expression ratio according to chromosomal location. Mean expression ratio (Ts1Cje/euploid) was significant only with Mmu16b genes (mean = 1.38, p < 0.001, t-test). Mmu16a and Mmu16b refer to euploid and three-copy genes in the Ts1Cje mice respectively.0.05 threshold (5 ) on the gene list and found no significant gene at all time points, not even three-copy genes. By increasing the FDR threshold up to 0.40 we found only 47 significant genes among which 6 are three-copy genes (Additional file 3, genes in grey boxes). These results suggest a limited secondary effect of trisomy on euploid genes. Most three-copy genes were not found significantly differentially expressed suggesting that compensatory mechanisms take place during postnatal development. Only 6 three-copy genes were constantly over-expressed in the cerebellum of Ts1Cje mice at P0, P3, P7 and P10. Using qPCR, we confirmed the increased expression of six threecopy genes at P0. Four of these genes (Atp50, Ifngr2, Sod1 and Son) were also found over-expressed in the study of Mao et al. conducted on DS foetal tissues, which included three cerebella [9]. We then performed a second transcriptome analysis using dissected cerebellar regions enriched in granule cell precursors from 9 Ts1Cje and nine euploid mice at P0, at the time when we observed a significant decrease of cell proliferation. About 4 of all genes were significantly differentially expressed in Ts1Cje samples as compared to euploid samples. This value was close the ones obtained in the entire cerebellum at P0, P3, P7 or P10. All the expressed three-copy genes (35) were significantly overexpressed in Ts1Cje with 12genes showing expression ratio significantly lower than 1.5 (t-test, = 5 , data not shown). After multi-test correction using the FDR procedure, 32 genes were still significantly modulated in Ts1CjeBMC Genomics 2009, 10:http://www.biomedcentral.com/1471-2164/10/Figure Ts1Cje and euploid mice at P0 layer 5 PCA of gene expression data from the external granule cell PCA of gene expression data from the external granule cell layer of Ts1Cje and euploid mice at P0. Principal Component Analysis on 11 305 genes expressed in the external granule cell layer at P0 (A) and on the 41 t.
