New cerebellar phenotypes in YAC transgenic mouse in vivo library of human Down syndrome critical region-1.

Down syndrome (DS) is the most frequent genetic cause of mental retardation (MR) associated with neurological alterations. To allow a genetic dissection of DS phenotype, we studied eight transgenic mouse lines carrying YACs containing human DNA fragments covering DS critical region (DCR-1), as an in vivo library. Herein, we found an increased brain size in the 152F7-mice containing DYRK1A gene. We also identified a new cerebellar alteration in two independent lines carrying 230E8-YAC. These mice showed significant elongation of the cerebellar antero-posterior axis (p<0.001), determined by increased length of rostral folia of the vermis (lobule II-V, p<0.0001; lobule VI, p<0.001). In addition, we identified a major neurological defect in culmen and declivus lobules in the 230E8-mice. We analyzed P30, P12, and P9 stages and detected high significant increased lengths of anterior lobules (II-VI) of 230E8-mice at P30 and P12 (lobule II-V, p<0.0001; lobule VI, p<0.05), but not at P9, indicating that this new phenotype appears between P9 and P12. Interestingly, 230E8-mice also present increased cortical cell density and mild learning defects. 230E8-YAC contains seven genes, some of which could be potentially responsible for this phenotype. Between them, we proposed DOPEY2 as potential candidate gene for these cerebellar alterations considering its high expression in the brain and that its homologous genes in yeast, Caenorhabditis elegans and Drosophila are involved in morphogenesis, suggesting a conserved role of DOPEY2 as a patterning gene.