Down Syndrome Abstract
of the Month:
Nov 1997
Functional screening and complex traits: human 21q22.2 sequences affecting learning in mice
Smith DJ; Rubin EM
Hum Mol Genet 1997;6(10):1729-33
Human Genome Center, Lawrence Berkeley National Laboratory, CA, USA.
Abstract:
Libraries of the mammalian genome have generally been propagated in single cells and have been used for gene discovery through in vitro analyses. We have expanded upon this concept by the creation of panels of YAC transgenic mice propagating targeted megabase regions of the genome. Such a panel of mice can be called an 'in vivo library' and genes can be identified based on functional screens of members of the library. To test this approach, we created a 2 Mb in vivo library of human chromosome 21q22.2. Analysis of the library has revealed that one 570 kb YAC, in two separate founder lines, was associated with distinct learning deficits compared with the other 21q22 YAC transgenics and non-transgenic control animals. We have localized the gene on the YAC that causes the deficits by taking advantage of fragmentation of the YAC during the process of microinjection. The responsible gene is the human minibrain gene, and the homolog of the gene in Drosophila is also associated with learning defects. These results suggest that altered dosage of minibrain is associated with abnormal neural development in flies and mice and, in humans, may also be involved in the molecular pathology of Down syndrome.
My comments:
This was a beautiful study. The researchers took the section of chromosome 21 most identified with DS (2 million base pairs of DNA) and cleaved it into 4 fragments, then injected each fragment into a different mouse. After making sure the mice were expressing the involved genes, the mice were subjected to a series of tests designed to elicit memory and learning behavior. Two mice had no difficulties, one mouse had mild deficits and one had severe deficits. The mouse with mild deficits was found to have an increased density of neurons in the brain, interfering with learning, but not indicative of the anatomy of DS. The mouse with severe learning deficits had a fragment of chromosome 21 which was further fragmented and injected into mice. Tests showed that the only fragment that caused learning deficits was a fragment whose only gene was the DYRK (minibrain) gene.Along with previous studies over the last year, this seems to confirm that cognitive difficulties and learning deficits in DS is due mainly to the DYRK gene. The DYRK gene, in normal amounts, is necessary for normal brain development in the fetus. Too much of the gene apparently interferes with normal brain development.
Other references regarding the DYRK gene:
Down syndrome-critical region contains a gene homologous to Drosophila sim expressed during rat and human central nervous system development. Dahmane N et al. Proc Natl Acad Sci USA 92: 9191-9195, 1995.
Cloning of a human homolog of the Drosophila Minibrain/rat Dyrk gene from the "Down syndrome critical region" of chromosome 21. Shindoh N et al. Biochem Biophys Res Comm 225:92-99, 1996.
Isolation of human and murine homologues of the Drosophila minibrain gene: human homologue maps to 21q22.2 in the Down syndrome "critical region". Song WJ; Sternberg LR; et al. Genomics 1996 Dec 15;38(3):331-9
Localisation of a human homologue of the Drosophila mnb and rat Dyrk genes to Chromosome 21q22.2. Chen H; Antonarakis SE. Hum Genet 99:262-265, 1997.