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

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

The SIB Swiss Institute of Bioinformatics' resources: focus on curated databases

The SIB Swiss Institute of Bioinformatics (www.isb-sib.ch) provides world-class bioinformatics databases, software tools, services and training to the international life science community in academia and industry. These solutions allow life scientists to turn the exponentially growing amount of data into knowledge. Here, we provide an overview of SIB's resources and competence areas, with a strong focus on curated databases and SIB's most popular and widely used resources. In particular, SIB's Bioinformatics resource portal ExPASy features over 150 resources, including UniProtKB/Swiss-Prot, ENZYME, PROSITE, neXtProt, STRING, UniCarbKB, SugarBindDB, SwissRegulon, EPD, arrayMap, Bgee, SWISS-MODEL Repository, OMA, OrthoDB and other databases, which are briefly described in this article

A mild and efficient preparation of <i>cis</i>-1,2-diols from 1,2,4-trioxanes

3,3-Unsubstituted cis-fused bicyclic 1,2,4-trioxanes, on treatment with benzylamine, gave the corresponding cis-1,2-diols in 85-99% yield.</p

Electrophile-induced rearrangement of 1,2,4-trioxanes. Formation of 1-benzofuran and 2<i>H</i>-1-benzopyrans

3,3,6,10b-Tetramethyl-4a,10b-dihydronaphtho[2,1-e][ 1,2,4]trioxane and its 3,3-spirocyclic cyclopentane analogue on treatment with an excess of trimethylsilyl trifluoromethanesulphonate for 10 min at 24 °C rearrange to give 2-(2-oxopropyl)-3-methyl-1-benzofuran in high yield; in similar fashion the 3-methyl, n-butyl, and phenyl derivatives of 3,10b-epidioxy-2,3,4a,10b-tetrahydro-6-methyl-1H-naphtho[2,1-b] pyran give the 3-oxobutyl, 3-oxoheptyl, and 3-phenyl-3-oxopropyl derivatives of 2-formyl-3-methyl(2H)-1-benzopyran.</p

1,2,4-trioxanes as masked, dual purpose, functional groups

1,2,4-Trioxanes readily undergo reductive cleavage upon treatment with zinc and acetic acid to furnish the corresponding 1,2-diols and C3-derived carbonyl compounds in high yield

The reaction of trimethylsilyl α-trimethylsilylperoxy esters with ketones and aldehydes. A simple, efficient synthesis of 1,2,4-trioxan-5-ones

The title compounds readily react in the presence of a catalytic amount of trimethylsilyl trifluoromethanesulphonate to give the corresponding 3,6-substituted 1,2,4-trioxan-5-ones in good yields.</p

Functionalization of the methyl group of 1,4-dimethyl-1,4-dihydronaphthalene-1,4-endoperoxide

The acid-catalysed cleavage of 1,4-dimethyl-1,4-dihydronaphthalene-1,4-endoperoxide gives the 4-hydroxy, methoxy, trifluoroacetoxy, formyloxy, bromo, and chloro methyl derivatives of 1-methylnaphthalene in yields of 36,38,52,76,77, and 100% respectively when water, methanol, trifluoracetic, formic, hydrobromic, or hydrochloric acids are used as reagents