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Tejedor, F. et al. minibrain: a new protein kinase family involved in postembryonic neurogenesis in Drosophila. Neuron 14, 287-301

Consejo Superior de Investigaciones Científicas, Instituto Cajal, Madrid, Spain.
Neuron (Impact Factor: 15.05). 03/1995; 14(2):287-301. DOI: 10.1016/0896-6273(95)90286-4
Source: PubMed

ABSTRACT

The development of the adult central nervous system of Drosophila requires a precise and reproducible pattern of neuroblast proliferation during postembryonic neurogenesis. We show here that mutations in the minibrain (mnb) gene cause an abnormal spacing of neuroblasts in the outer proliferation center (opc) of larval brain, with the implication that mnb opc neuroblasts produce less neuronal progeny than do wild type. As a consequence, the adult mnb brain exhibits a specific and marked size reduction of the optic lobes and central brain hemispheres. The insufficient number of distinct neurons in mnb brains is correlated with specific abnormalities in visual and olfactory behavior. The mnb gene encodes a novel, cell type-specific serine-threonine protein kinase family that is expressed and required in distinct neuroblast proliferation centers during postembryonic neurogenesis. The mnb kinases share extensive sequence similarities with kinases involved in the regulation of cell division.

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    • "Among the genes from this 33-gene region, Dyrk1a is an attractive candidate for inducing cognitive impairment phenotypes. DYRK1A, the mammalian ortholog of Drosophila minibrain kinase (mnb) (Tejedor et al., 1995), encodes a proline/arginine-directed serine/threonine kinase. Both in trisomic mice and in individuals with DS, brain levels of DYRK1A are increased approximately 1.5-fold, indicating that this protein is overexpressed in a gene dosage-dependent manner (Dowjat et al., 2007). "

    Full-text · Dataset · Oct 2015
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    • "Among the genes from this 33-gene region, Dyrk1a is an attractive candidate for inducing cognitive impairment phenotypes. DYRK1A, the mammalian ortholog of Drosophila minibrain kinase (mnb) (Tejedor et al., 1995), encodes a proline/arginine-directed serine/threonine kinase. Both in trisomic mice and in individuals with DS, brain levels of DYRK1A are increased approximately 1.5-fold, indicating that this protein is overexpressed in a gene dosage-dependent manner (Dowjat et al., 2007). "
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    ABSTRACT: Cognitive impairment in Down syndrome (DS) has been linked to increased synaptic inhibition. The underlying mechanisms remain unknown, but memory deficits are rescued in DS mouse models by drugs targeting GABA receptors. Similarly, administration of epigallocatechin gallate (EGCG)-containing extracts rescues cognitive phenotypes in Ts65Dn mice, potentially through GABA pathway. Some developmental and cognitive alterations have been traced to increased expression of the serine-threonine kinase DYRK1A on Hsa21. To better understand excitation/inhibition balance in DS, we investigated the consequences of long-term (1-month) treatment with EGCG-containing extracts in adult mBACtgDyrk1a mice that overexpress Dyrk1a. Administration of POL60 rescued components of GABAergic and glutamatergic pathways in cortex and hippocampus but not cerebellum. An intermediate dose (60 mg/kg) of decaffeinated green tea extract (MGTE) acted on components of both GABAergic and glutamatergic pathways and rescued behavioral deficits as demonstrated on the alternating paradigm, but did not rescue protein level of GABA-synthesizing GAD67. These results indicate that excessive synaptic inhibition in people with DS may be attributable, in large part, to increased DYRK1A dosage. Thus, controlling the level of active DYRK1A is a clear issue for DS therapy. This study also defines a panel of synaptic markers for further characterization of DS treatments in murine models.
    Full-text · Article · Oct 2015 · Frontiers in Behavioral Neuroscience
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    • "In humans, truncating mutations in the DYRK1A gene cause primary microcephaly (Courcet et al., 2012) and autism (O'Roak et al., 2012). Moreover, mice and flies with haploinsufficiency of the Dyrk1a/minibrain genes have smaller brains (Fotaki et al., 2002; Tejedor et al., 1995), indicating that the role of DYRK1A in brain growth is conserved across evolution. Experiments on neural progenitors derived from induced pluripotent stem cells from monozygotic twins discordant for trisomy 21 highlight DYRK1A as one of the chromosome 21 genes important for the proliferation and differentiation defects associated with DS (Hibaoui et al., 2014). "
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    ABSTRACT: Alterations in cerebral cortex connectivity lead to intellectual disability and in Down syndrome, this is associated with a deficit in cortical neurons that arises during prenatal development. However, the pathogenic mechanisms that cause this deficit have not yet been defined. Here we show that the human DYRK1A kinase on chromosome 21 tightly regulates the nuclear levels of Cyclin D1 in embryonic cortical stem (radial glia) cells, and that a modest increase in DYRK1A protein in transgenic embryos lengthens the G1 phase in these progenitors. These alterations promote asymmetric proliferative divisions at the expense of neurogenic divisions, producing a deficit in cortical projection neurons that persists in postnatal stages. Moreover, radial glial progenitors in the Ts65Dn mouse model of Down syndrome have less Cyclin D1, and Dyrk1a is the triplicated gene that causes both early cortical neurogenic defects and decreased nuclear Cyclin D1 levels in this model. These data provide insights into the mechanisms that couple cell cycle regulation and neuron production in cortical neural stem cells, emphasizing that the deleterious effect of DYRK1A triplication in the formation of the cerebral cortex begins at the onset of neurogenesis, which is relevant to the search for early therapeutic interventions in Down syndrome.
    Full-text · Article · Feb 2015 · EBioMedicine
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