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.
During development of the nervous system, specific recognition molecules provide the cues necessary for the formation of neural connections. In some regions, guiding cues for axonal pathfinding and target selection are provided by specific cells that exist only transiently during development, such as the floorplate or the cortical subplate. In the hippocampus, distinct groups of fibres innervate different layers. We have tested the hypothesis that transient neurons in the hippocampus provide positional information for the targeting of these fibres. Here we report that ablation of Cajal-Retzius cells in organotypic slice cultures of hippocampus prevented the ingrowth of entorhinal but not of commissural afferents. Experiments inhibiting Reelin (an extracellular matrix protein expressed by Cajal-Retzius cells) and analysis of reeler mutant mice showed dramatic abnormalities in the development of entorhinal afferents. Thus Cajal-Retzius cells and reelin are essential for the formation of layer-specific hippocampal connections.
By Alu-splice PCR we have trapped two exons and subsequently identified the full length cDNA of a human gene, Intersectin (ITSN), which maps to chromosome 21q22.1 between markers D21S320 and D21S325. The gene has the potential to code for at least two different protein isoforms by alternative splicing (ITSN-L and ITSN-S). Intersectin exists with a high degree of similarity in flies, frogs and mammals, suggesting a conserved role in higher eukaryotes. Analysis of the expression pattern of human and mouse Intersectin detected mRNAs in all adult and foetal tissues tested, with the longer isoform present in brain. In situ hybridisation studies in the developing mouse brain showed ITSN expression in both proliferating and differentiating neurons. The genomic structure of ITSN was determined using the chromosome 21 sequences deposited in the public databases. The protein contains several known motifs which implicate ITSN in clathrin mediated endocytosis and synaptic vesicle recycling. The expression pattern of Intersectin in mouse brain, its presumed function and its overexpression in brains from Down syndrome patients, suggest that Intersectin may contribute in a gene dosage-dependent manner to some of the abnormalities of Down syndrome.
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