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b'The Drosophila gene minibrain codes for a protein kinase. Mutants with a reduced expression of minibrain are characterised by a strongly reduced brain size and learning and memory deficits. Dyrk1A is the mammalian homologue of minibrain; the encoded protein is the founding member of the family of Dyrk protein kinases. The human DYRK1A gene is implicated in the emergence of the cognitive deficits in Down syndrome, due to its location on chromosome 21 in the so-called Down syndrome critical region (DSCR), its overexpression in Down syndrome individuals and also because Dyrk1A-overexpressing mice show learning and memory deficits. Taken together, these data point to a gene dosage dependent function of Dyrk1A/minibrain in processes that are associated with cognitive functions such as learning and memory.\\nThe aim of this study was to elucidate the function of Dyrk1A in the adult mammalian brain. Three aproaches were chosen:\\nFirst, an analysis of the expression of Dyrk1A and of the intracellular localisation of the respective protein in the adult mouse brain was performed. Dyrk1A is expressed in several brain areas, e.g. in the neocortex, in the hippocampal formation and in the cerebellum. In neurons, Dyrk1A is located either mostly nuclear, or predominantly or even exclusively in the cytoplasm, depending on the region and on the type of neuron.\\nSecond, to characterise the gene dosis dependent function of Dyrk1A, it was intended to generate transgenic mice that express a third copy of Dyrk1A, as it is the case in human trisomy 21 (Down syndrome). These transgenic mice should express the third copy of Dyrk1A in a region- and time-specific manner, e.g. in principal neurons in the adult forebrain. This should avoid developmental defects and disturbances of, e.g., the motor system and should allow for the specific analysis of the role of Dyrk1A in learning and memory and in brain regions involved in cognitive processes. A BAC (bacterial artificial chromosome) clone containing the whole Dyrk1A locus was isolated. This BAC was modified by homologous recombination in E. coli (GET recombination) to render it suitable for the generation of transgenic mice. Furthermore, a recombination cassette for a second modification step was constructed to allow for the region- and time-specific expression of the Dyrk1A gene on the BAC.\\nThird, a yeast two-hybrid screen to identify proteins interacting with Dyrk1A was performed. Two of six clones obtained were shown to code for proteins interacting specifically with Dyrk1A: Sept4 (Pnutl2/H5/CDCrel-2), a GTPase of the Septin family, and Arip4, a steroid hormone receptor cofactor with ATP-dependent chromatin-remodelling activity. These interactions were confirmed in mammalian cells by coimmunoprecipitation. By in situ-hybridisation, the coexpression of Dyrk1A with the genes of both interactors was shown in various brain regions. In addition, Dyrk1A and Arip4 were shown to be colocalised in a speckle-like nuclear subcompartment in primary rat hippocampal neurons and in mammalian cell lines. These results point to an interaction of Dyrk1A with Arip4 also in vivo and implicate Dyrk1A in steroid hormone-mediated signalling. Furthermore, an interaction between Dyrk1A and Sept5/CDCrel-1, a close relative of Sept4, was shown. Sept5 is thought to play an inhibitory role in the fusion of synaptic vesicles with the presynaptic membrane and transmitter release.\\nThe results of this study contribute to the understanding of the role of Dyrk1A in physiological and pathophysiological contexts. Eventually, this should help (i) to elucidate the mechanisms that lead to mental retardation in Down syndrome and (ii) to develop tools to interfere with the function of Dyrk1A and to establish novel strategies for a therapy to alleviate mental retardation in Down syndrome.'