The Mouse Brain Transcriptome by SAGE: Differences in Gene Expression between P30 Brains of the Partial Trisomy 16 Mouse Model of Down Syndrome (Ts65Dn) and Normals

Abstract

Trisomy 21, or Down syndrome (DS), is the most common genetic cause of mental retardation. Changes in the neuropathology, neurochemistry, neurophysiology, and neuropharmacology of DS patients' brains indicate that there is probably abnormal development and maintenance of central nervous system structure and function. The segmental trisomy mouse (Ts65Dn) is a model of DS that shows analogous neurobehavioral defects. We have studied the global gene expression profiles of normal and Ts65Dn male and normal female mice brains (P30) using the serial analysis of gene expression (SAGE) technique. From the combined sample we collected a total of 152,791 RNA tags and observed 45,856 unique tags in the mouse brain transcriptome. There are 14 ribosomal protein genes (nine underexpressed) among the 330 statistically significant differences between normal male and Ts65Dn male brains, which possibly implies abnormal ribosomal biogenesis in the development and maintenance of DS phenotypes. This study contributes to the establishment of a mouse brain transcriptome and provides the first overall analysis of the differences in gene expression in aneuploid versus normal mammalian brain cells.

Glutamatergic synaptic deficits in the prefrontal cortex of the Ts65Dn mouse model for Down syndrome

“…However, the regulatory relationships between these genes are currently unknown, and overexpression of genes on chromosome 21 could lead to modified expression of genes on other chromosomes. While comparative analyses of gene expression on other chromosomes have demonstrated that gene deregulations are specific to Hsa21 in DS foetuses (Mao et al, 2003), research on the Ts65Dn model has shown that there is a global alteration in gene expression in these mice (Chrast et al, 2000;Lyle et al, 2004). Furthermore, gene products can interact with one another, creating compensatory or exacerbating mechanisms, which can affect synaptic parameters in Ts65Dn mice differently, reflecting the intricacy of the gene effects associated with this condition.…”

“…Nat Neurosci 10, 411-413. Gardiner, K., and Davisson, M. (2000). The sequence of human chromosome 21 and implications for research into Down syndrome.…”

Genomics and proteomics in solving brain complexity

“…SAGE has been widely used in neuroscience, either to generate global gene expression profile of specific neuronal regions, as in the case of a study that analyzed B30,000 unique mRNA transcripts in the rat hippocampus, 51 or in the case of comparative analysis of gene expression in normal and disease mammalian brain cells. 52,53 Major disadvantages of SAGE are the cost of sequencing and the biases introduced by the necessary cloning step. Another similar technique used to generate ESTs is the massively parallel signature sequencing (MPSS), 54 and is particularly useful for a quantitative view of the transcripts that are produced in cells.…”

Aspectos genómicos, transcriptómicos y del diagnóstico en el síndrome de Down

“…Este modelo fue previamente abordado por Chrast y colaboradores en 2000, en su estudio sobre el transcriptoma del cerebro del ratón, que dio pasos importantes en el entendimiento del modo en el que se expresan los genes y la inducción de enfermedades [28]. Asimismo, Mao y colaboradores en 2005 detectaron cambios específicos en la expresión génica, tanto en los tejidos como en las células en estado de trisomía 21 durante el desarrollo fetal, donde el análisis estadístico de los grupos de genes funcionales estudiados por microarreglos proporcionaron indicios de posibles vías biológicas afectadas por la trisomía 21 [29].…”