Search

Knowledge of the potential effect of genetic background in disease models is important. The SOD1-G93A transgenic mouse is the most widely used model in amyotrophic lateral sclerosis (ALS). Since these animals show considerable variability both in the onset and the progression of the disease, this study aimed to characterize the potential differences between the two most widely used strains, C56BL/6 (B6) and B6SJL. A rotarod test was carried out to assess strength and motor coordination, while electrophysiology tests were performed to evaluate the function of upper and lower motor neurons. Survival of the animals and motor neuron loss were also studied. The results did not show any background effect regarding the rotarod test, despite the differences in the pattern of decline in central and peripheral motor conduction. The onset of motor neuron abnormalities was later in B6SJL mice, but progressed more rapidly. Lifespan was longer for B6 than for B6SJL animals. In conclusion, background differences in disease onset and progression are important. The characteristics of the strain should be taken into account in experimental design of therapeutic studies.

DYRK1A is the human orthologue of the Drosophila minibrain (mnb) gene, which is involved in postembryonic neurogenesis in flies. Because of its mapping position on chromosome 21 and the neurobehavioral alterations shown by mice overexpressing this gene, involvement of DYRK1A in some of the neurological defects of Down syndrome patients has been suggested. To gain insight into its physiological role, we have generated mice deficient in Dyrk1A function by gene targeting. Dyrk1A / null mutants presented a general growth delay and died during midgestation. Mice heterozygous for the mutation (Dyrk1A / ) showed decreased neonatal viability and a significant body size reduction from birth to adulthood. General neurobehavioral analysis revealed preweaning developmental delay of Dyrk1A / mice and specific alterations in adults. Brains of Dyrk1A / mice were decreased in size in a region-specific manner, although the cytoarchitecture and neuronal components in most areas were not altered. Cell counts showed increased neuronal densities in some brain regions and a specific decrease in the number of neurons in the superior colliculus, which exhibited a significant size reduction. These data provide evidence about the nonredundant, vital role of Dyrk1A and suggest a conserved mode of action that determines normal growth and brain size in both mice and flies. Dual-specificity tyrosine-regulated kinases (DYRKs) are a novel subfamily of protein kinases that catalyze their autophosphorylation on tyrosine residues and the phosphorylation of serine/threonine residues on exogenous substrates (5, 7, 19). Their kinase activity depends on the presence of a YXY motif in the activation loop of the catalytic domain (20), which is located at the same position as the characteristic TXY motif of the mitogen-activated protein kinases (MAPKs), indicating a possible involvement of these proteins in signal transduction pathways similar to those of the MAPKs (26).