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Sökning: WFRF:(Kettunen Petronella) > Övrigt vetenskapligt/konstnärligt

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  • Farnsworth, Bryn, et al. (författare)
  • Morpholino knockdown of qkib leads to disturbed neural development in the larval zebrafish.
  • Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
    • Quaking (QKI) is a member of the Signal Transduction and Activation of RNA (STAR) protein family and has been found to regulate the splicing, quantity, and translation of mRNA. Several studies have also found an association of QKI with a variety of human neurological disorders, such as schizophrenia, ataxia, and Alzheimer’s disease, amongst others. Mouse mutants show clear developmental defects in myelin formation. Critical periods for the investigation of myelin aberration have been precluded by the embryonic lethality of Qk null mice mutants. We have previously shown that the zebrafish is a suitable tool in which to interrogate qki function. Within this study we employ a gene-knockdown approach with the use of morpholinos and the Tg(olig2:DsRed2), and Tg(-4.9sox10:eGFP) transgenic zebrafish lines, and confocal imaging. We find a reduction in the number of oligodendrocytes, critical for the formation of myelin. We also find aberrations in the development and arborization of motor neurons across the spinal cord, and a complete absence of eurydendroid cells within the cerebellum. These findings have parallels to both neuroanatomical evidence from viable Qk mutant mice, and to aspects of related human neurological disease.
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  • Farnsworth, Bryn, et al. (författare)
  • QKI6B is upregulated in schizophrenic brains and predicts GFAP expression
  • Ingår i: Schizophrenia Research. - 0920-9964 .- 1573-2509.
  • Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
    • Schizophrenia is a highly heritable disorder with a heterogeneous symptomatology. Research increasingly indicates the importance of the crucial and often overlooked glial perturbations within schizophrenic brains. Within this study, we examined an isoform of quaking (gene encoding an RNA-binding protein that is exclusively expressed in glial cells), known as QKI6B, and an astrocyte marker glial fibrillary acidic protein (GFAP), postulated to be under the regulation of QKI. The expression levels of these genes were quantified across post-mortem samples from the prefrontal cortex of 55 schizophrenic brains, and 55 healthy control brains, using real-time PCR. We report, through an analysis of covariance (ANCOVA) model, an upregulation of both QKI6B, and GFAP in the prefrontal cortex of schizophrenic brains. Previous research has suggested that the QKI protein directly regulates the expression of several genes through interaction with a motif in the target’s sequence, termed the Quaking Response Element (QRE). We therefore examined if QKI6B expression can predict the outcome of GFAP, and several oligodendrocyte-related genes, using a multiple linear regression approach. We found that QKI6B significantly predicts, and possibly regulates the expression of GFAP, but does not predict oligodendrocyte-related gene outcome, as previously seen with other QKI isoforms. 
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  • Kettunen, Petronella (författare)
  • Neuromodulation within a spinal locomotor network : role of metabotropic glutamate receptor subtypes
  • 2004
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • The metabotropic glutamate receptors, mGluRs, are G-protein coupled receptors. They consist of eight cloned subtypes, which are divided into three groups depending on the amino acid sequence similarity, pharmacology and their signal pathways. In the lamprey spinal cord, group I mGluRs are located postsynaptically, while group II and III are presynaptic and depress synaptic transmission. The goal of this thesis has been to elucidate the mechanisms by which the two subtypes of group I mGluRs, i.e. mGluR1 and mGluR5, modulate the firing properties of single neurons, the synaptic interactions and the overall activity of the spinal locomotor network in the lamprey. mGluR1 activation by endogenously released glutamate increases the frequency of the locomotor rhythm induced by NMDA in the isolated lamprey spinal cord preparation. This increase in the frequency is the result of a number of cellular and molecular mechanisms that have been studied in detail. Firstly, mGIuR1 potentiates the NMDA-induced current and modulates NMDAinduced TTX-resistant membrane potential oscillations known to occur during locomotion. Mathematical simulations of the interaction between mGluR1 and NMDA receptors reproduce the modulation of the NMDA-induced oscillations and the increase in the locomotor frequency. Secondly, mGluR1 activation depolarizes the membrane potential of neurons and consequently induces repetitive firing. These effects are due to an inhibition of a leak current responsible for setting the resting membrane potential. Interestingly, mGluR1 activates different signaling pathways to modulate NMDA current and leak conductance. Both effects require activation of Gproteins. The mGluR1-mediated inhibition of leak current requires PLC activation and release of Ca2+ from internal stores, as well as tyrosine kinase activation. The potentiation of NMDA current is not, however, dependent on an increase in intracellular Ca2+ or on tyrosine kinases. Thirdly, activation of mGluR1 receptors gives rise to a synthesis and release of endocannabinoids from postsynaptic neurons. The released endocannabinoids act as retrograde messengers which bind to presynaptic receptors and reduce glycinergic synaptic transmission. The reduced inhibitory transmission will result in an increase in the locomotor frequency. Hence, mGluR1 activation triggers the release of endocannabinoids which thus contribute to the mGlur1 mediated modulation of the locomotor network operation. Finally, endogenous activation of mGluR5 during locomotion decreases the burst frequency and produces long-lasting oscillations of the intracellular Ca2+ concentration. These oscillations are mediated through PLC and Ca2+ release from internal stores. Furthermore, they are also dependent on Ca2+ influx through L-type Ca2+ channels but do not involve PKC activation. Thus, mGluR5 seems to modulate the locomotor frequency via mechanisms involving oscillations of intracellular Ca 2+ concentration. In conclusion, the two group I mGluRs subtypes, mGluR1 and mGluR5, use separate signaling pathways and mediate opposite effects on locomotor activity. While the modulatory effects of mGluR5 seems to involve Ca2+ oscillations, those of rnGluR1 depend on different cellular and synaptic mechanisms which act in a synergistic manner to regulate the locomotor frequency.
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  • Resultat 1-5 av 5

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