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.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:628267 |
| Date | January 2013 |
| Creators | Gajendra, Sangeetha |
| Publisher | King's College London (University of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://kclpure.kcl.ac.uk/portal/en/theses/molecular-regulation-of-neuroblast-migration-in-the-postnatal-brain(055c4407-fb25-436a-91f6-e5fdf2fb42d1).html |
Page generated in 0.0069 seconds