Molecular regulation of neuroblast migration in the postnatal brain

The subventricular zone (SVZ) is one of the main neurogenic niches in the postnatal<br/>brain. Neural precursors derived from SVZ stem cells migrate in chains to the<br/>olfactory bulb (OB) via the rostral migratory stream (RMS) through channels (glial<br/>tubes) formed by the processes of astrocytes. Importantly, these precursors have<br/>the capacity to migrate away from their native route to areas of pathological<br/>damage in the adult brain. Therefore, studying the migratory properties of these<br/>cells is essential, not only to understand basic aspects of adult neurogenesis, but<br/>also to exploit the potential of adult neural stem cells in neuroregenerative<br/>strategies. Whilst considerable progress has been made in the field of SVZ neural<br/>precursor migration, the exact molecular mechanisms regulating this process<br/>remain to be fully elucidated.<br/><br/>The endocannabinoid system is known to play an important role in the regulation of<br/>neural stem cell proliferation. Here, we show that CB signalling also regulates the<br/>migration of SVZ-derived neural precursors. In addition, stimulation of G-protein<br/>coupled cannabinoid receptors, CB1 and CB2, leads to significant activation of RalA,<br/>a Ras-like GTPase involved in the control of neuronal morphology and polarity.<br/>siRNA-mediated knockdown of RalA or the expression of dominant negative RalA<br/>abolished cannabinoid-induced stimulation of migration. Time-lapse imaging<br/>revealed that depletion of RalA strongly impaired nucleokinesis: a crucial step for<br/>efficient migration. Analysis of RalA function in vivo, using wild type and mutant<br/>constructs electroporated into the SVZ, showed that the loss of RalA function<br/>results in both altered morphology and direction of migration. Finally, selective<br/>deletion of RalA in RMS neuroblasts in vivo further confirms that RalA is required<br/>for correct polarised morphology of migrating neuroblasts in the RMS.<br/><br/>In summary, RalA is activated by CB agonists, and is required for CB-promoted<br/>migration of RMS neuroblasts. Furthermore, RalA expression is necessary for<br/>polarised morphology and efficient migration of RMS neuroblasts both in vitro and<br/>in vivo.

Name dc:type.qualificationname

Doctor of Philosophy

Level dc:type.qualificationlevel

Doctoral Thesis

Grantor dc:publisher.institution

King's College London

Year dc:date.issued

2013

Author dc:creator

• Gajendra, Sangeetha

Advisors dc:contributor.advisor

• Doherty, Patrick
• Lalli, Giovanna

Language dc:language

eng

Identifier

oai:kclpure.kcl.ac.uk:studenttheses/055c4407-fb25-436a-91f6-e5fdf2fb42d1

OAI identifier oai:identifier

oai:kclpure.kcl.ac.uk:studenttheses/055c4407-fb25-436a-91f6-e5fdf2fb42d1