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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.
Original languageEnglish
Awarding Institution
Award date1 Jan 2013

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