Chromosome 21q is estimated to contain 500-1000 genes, and an unknown number of these are involve din the development of the own Syndrome phenotype. In addition, it is expected that many genes on chromosome 21 interact with genes or gene products located elsewhere in the genome, thus producing a cascade of further effects. Ameliorating the effects of trisomy 21 will require understanding of the genes involved. In this component, we are proposing two approaches to examine the complexity of the Down Syndrome phenotype at the gene level. (1) Under current funding of this program project, we have obtained information on a large percentage of 21q genes. From this information, we now propose further study of several genes by means of transgenic mouse construction. Each genes has been chosen because over expression is associated with a compelling hypothesis for relevance to the Down Syndrome phenotype. Genes include a transcription factor, GABPA known to be involved in the regulation of expression of a wide variety of genes; in RNA editase, RED1, known to edit glutamate receptor subunits and affect their physiological functioning; a glutamate receptor subunit, GLuR5; and a putative pre-mRNA processing enzyme, rA4, a novel member of a gene family known to affect patterns in alternative splicing. Over expressing transgenic mice for each gene will be examined at the molecular level in this component, and in collaboration with the Transgenic Mouse Core and the Mouse Behavior Core, for gross anatomical and behavioral phenotypic effects, and in collaboration with the Davisson component, for electrophysiological abnormalities. In this way, we will determine what role, if any, these genes may play in neurological development and/or the mental retardation and cognitive deficits od Down Syndrome. (2) We will use differential display to characterize the alterations in gene expression caused by segmental trisomies and trisomy of single genes. The segmental trisomies will include both the Ts65Dn and Ts232Dn partial trisomy 16 mice of the Davisson component, and associated Cre/lox deletions constructed in the Berennan component, as well as the mouse chromosome 10 and 17 region Cre/lox partial trisomies constructed in the Brennan component. Single gene transgenics will include the four constricted in this component and a ETS2 transgenic already available. Strains will be prioritized for study based on phenotypic assessments carried out in Brennan, Crnic, Davisson and Gardiner cores and components. We will characterize the number and the natures of the genes altered in expression level and attempt to deduce patterns and biological relevance. Both of these approaches will increase our understanding of neurological development in general, and will define the molecular basis of Down Syndrome mental retardation in particular. Results will also aid in future discussions relating to clinical intervention potentials.
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