Table 1.

A comparative transcriptomic analysis of the brain with DS.

Sample (Genetic Background)	Tissue	Number of Samples	Stage	Method	Transcription of Trisomic Genes	Remarks	Reference
Human	Cerebellum	Control: n = 3; DS: n = 3	18–20 weeks of gestation	Affymetrix U133A GeneChip	A gene dosage-dependent increase in transcription was detected in the cerebellum of individuals with DS.		[11]
Human	Dorsolateral prefrontal cortex	Control: n = 8; DS: n = 7	Adult	Affymetrix human genome HG-U133A GeneChip	More than 25% of genes on HSA21 were differentially expressed, versus a median of 4.4% for all chromosomes.	Dysregulated genes are classified into development (notably Notch and Dlx family genes), lipid transport, and cellular proliferation.	[12]
Ts65Dn mice (B6Ei/C3)	Whole brain	Control: n = 7, 4 males, 3 males Ts65Dn: n = 3, 3 males	Postnatal day 30	SAGE analysis with library (28,531 tags)	The expression of most known genes from the trisomic region of mouse MMU16 in Ts65Dn is too low. Only three genes (Ifnar2, Ufngr2, and Cbr) are overexpressed in Ts65Dn males compared to control males.	It has been suggested that abnormal ribosomal biogenesis may be involved in the development and maintenance of DS phenotypes.	[13]
Ts65Dn mice (B6Ei/C3)	Cerebellum, cortex, midbrain	Control: n = 8 Ts65Dn: n = 8	Males at 1–4 months old	Quantitative real-time RT-PCR	A trend toward 1.5-fold over-expression for the trisomic genes was detected. The global over-expression level of trisomic genes in Ts65Dn was 1.44-fold in the cerebellum, 1.37-fold in the cortex, and 1.39-fold in the midbrain.		[14]
Ts65Dn mice (B6Ei/C3)	CA1 pyramidal cells	Control: n = 7; Ts65Dn: n = 9	4–9 months old	Custom-designed array (576 cDNA/ESRs)	N/A	Downregulation of neutrophins and their cognate neutrophin receptors.	[15]
Ts65Dn mice (B6Ei/C3)	Cerebellum	Control (sedentary): n = 4 Control (running): n = 4 Ts65Dn (sedentary) n = 4 Ts65Dn (running): n = 4	Females at 9–13 months old	Agilent oligonucleotide microarray (SurePrint G3 Mouse Gene Expression 8 × 60 K Microarray)	Forty tested trisomic genes showed higher expression in Ts65Dn mice than in euploid mice, with an average ratio of Ts65Dn/WT 1.47.		[16]
Ts65Dn mice (B6Ei/C3)	CA1 pyramidal cells	Control: n = 12 Ts65Dn: n = 13	10–24 months old	Custom-designed array (576 cDNA/ESRs)	N/A	Dysregulation of excitatory and inhibitory neurotransmission receptor families and neurotrophins, including brain-derived neurotrophic factor, as well as several cognate neurotrophin receptors.	[17]
Ts1Cje mice (C57BL/6J)	Fetal brain	Control: n = 5 Ts1Cje: n = 5	Embryonic day 15.5	Affymetrix mouse gene 1.0 ST arrays	About half of the trisomic genes were significantly upregulated in the embryonic brain of Ts1Cje mice.		[18]
Ts1Cje mice (C57BL/6J)	Whole brain	Control: n = 6 Ts1Cje: n = 6	Males at postnatal day 0	Affymetrix murine genome U74A and U74B microarrays	The expression of most genes in the trisomic region was increased approximately 1.5-fold, and the top 24 most consistently over-expressed genes in Ts1Cje mice were all located in the trisomic region.	The transcripts of trisomic genes were mainly overexpressed in a gene-dose-dependent manner.	[19]
Ts1Cje mice (C57BL/6)	Cerebellum	Control: n = 2 for each stage Ts1Cje: n = 2 for each stage	Postnatal day 0, 15, and 30	Affymetrix murine genome U74A version	The mean expression ratios of trisomic genes between Ts1Cje and controls were 1.66, 1.32, and 1.32 at P0, P15, and P30, respectively, whereas with euploid genes, the ratios were 1.08, 1.12, and 1.02 at P0, P15, and P30, respectively.	In the cerebellum of Ts1Cje mice, six homeobox genes and two genes belonging to the Notch pathway showed severely decreased expression	[20]
Ts1Cje mice (B6C3SnF1/ Orl)	Cerebellum	Control: n = 2 for each stage Ts1Cje: n = 2 for each stage	Postnatal day 0, 3, 7, and 10	Agilent RNA 6000	A prevailing gene dosage effect of trisomy and a limited secondary effect on postnatal development were noted. Approximately 80% of gene expression differences were attributed to dosage imbalance, suggesting that the trisomic genes are likely to be directly responsible for the phenotype present in cerebellum of Ts1Cje mice.		[21]
Ts1Cje mice (C57BL/6)	Cerebral cortexcerebellum hippocampus	Control: n = 3 for each stage Ts1Cje: n = 3 for each stage	Postnatal day 1, 15, 30, and 84	Affymetrix murine genome U74A version 3 microarray	A gene dosage-dependent increase in transcription was detected in the cerebellum of individuals with DS.	The Jak-Stat pathway may be overstimulated in the brain of Ts1Cje mice.	[22]
Ts1Cje mice (C57BL/6J)	Cerebral cortex hippocampus	Control: n = 5 Ts1Cje: n = 6	Females at 2–2.5 months old	Affymetrix mouse gene 1.0 ST arrays	Of the 77 genes present in the trisomic region of Ts1Cje mice, 22 (28.6%) were differentially regulated in either the cortex or hippocampus, while the expression of the remaining 46 (71.4%) was not affected.	Dysregulation of NFAT signaling, and G-protein signaling (e.g., olfactory perception)	[23]
Ts1Cje mice (B6C3SnF1/Orl)	Neural progenitor cells	Control: n = 3 Ts1Cje: n = 3	Neurospheres were derived from E14.5 cortex	DNA microarrays (RNG-MRC_MM25k_EVRY)	The expression ratios of 54% of trisomic genes (Ts1Cje/WT) were significantly higher than the expected diploid gene ratio of 1.0.	Ts1Cje neural progenitors proliferated at a slower rate. Some euploid genes involved in proliferation, differentiation, and the glial function were dysregulated.	[24]