Molecular regulation of neuroblast migration in the postnatal brain

    Student thesis: Doctoral ThesisDoctor of Philosophy


    The subventricular zone (SVZ) is one of the main neurogenic niches in the postnatal
    brain. Neural precursors derived from SVZ stem cells migrate in chains to the
    olfactory bulb (OB) via the rostral migratory stream (RMS) through channels (glial
    tubes) formed by the processes of astrocytes. Importantly, these precursors have
    the capacity to migrate away from their native route to areas of pathological
    damage in the adult brain. Therefore, studying the migratory properties of these
    cells is essential, not only to understand basic aspects of adult neurogenesis, but
    also to exploit the potential of adult neural stem cells in neuroregenerative
    strategies. Whilst considerable progress has been made in the field of SVZ neural
    precursor migration, the exact molecular mechanisms regulating this process
    remain to be fully elucidated.

    The endocannabinoid system is known to play an important role in the regulation of
    neural stem cell proliferation. Here, we show that CB signalling also regulates the
    migration of SVZ-derived neural precursors. In addition, stimulation of G-protein
    coupled cannabinoid receptors, CB1 and CB2, leads to significant activation of RalA,
    a Ras-like GTPase involved in the control of neuronal morphology and polarity.
    siRNA-mediated knockdown of RalA or the expression of dominant negative RalA
    abolished cannabinoid-induced stimulation of migration. Time-lapse imaging
    revealed that depletion of RalA strongly impaired nucleokinesis: a crucial step for
    efficient migration. Analysis of RalA function in vivo, using wild type and mutant
    constructs electroporated into the SVZ, showed that the loss of RalA function
    results in both altered morphology and direction of migration. Finally, selective
    deletion of RalA in RMS neuroblasts in vivo further confirms that RalA is required
    for correct polarised morphology of migrating neuroblasts in the RMS.

    In summary, RalA is activated by CB agonists, and is required for CB-promoted
    migration of RMS neuroblasts. Furthermore, RalA expression is necessary for
    polarised morphology and efficient migration of RMS neuroblasts both in vitro and
    in vivo.
    Date of Award1 Jan 2013
    Original languageEnglish
    Awarding Institution
    • King's College London
    SupervisorPatrick Doherty (Supervisor) & Giovanna Lalli (Supervisor)

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