The role of retinoic acid in adult neurogenesis

Student thesis: Doctoral ThesisDoctor of Philosophy

Abstract

Retinoic acid (RA is a biologically active derivative of vitamin A, and has important functions in the postnatal brain. One of these is the regulation of adult neurogenesis, the process whereby neural stem cell (NSCs) divide to produce new neurons in the adult brain. However, the exact mechanisms by which RA governs proliferation, differentiation and migration during adult neurogenesis are yet to be defined. Furthermore, the specific receptors involved in RA signalling during adult neurogenesis have not been identified. In fact, the expression patterns of RARs and RXRs have not been fully described in the specific niches of the brain where adult neurogenesis occurs; the dentate gyrus (DG) and subventricular zone (SVZ). In addition, RA signalling in the brain has been shown to decline with age, and play a role in the pathogenesis of age-related neurodegenerative disorders, such as Alzheimer’s Disease (AD). Adult neurogenesis also declines with age. Therefore, we hypothesised that RA signalling may play a role in the age-related decline of adult neurogenesis.

Firstly, we describe here the expression patterns of retinoic acid receptors (RARs), retinoid receptor (RXRs) and supporting metabolic and catabolic enzymes in the adult SVZ and DG. Further immunofluorescence double!labelling studies demonstrate that RARα and RARβ specifically are expressed in neural progenitor cells (NPCs) of the SVZ and DG. Expression studies also revealed the presence of RA signalling proteins in the rostral migratory stream (RMS), along which neuroblasts from the SVZ migrate to the of factory bulb (OB). However, evidence from further in vivo and in vitro investigations conclude that RA signalling does not control the migration of neuroblasts in the adult brain. Nevertheless, blockade of RARs with a small molecule significantly exacerbated the age-related decline of adult neurogenesis. Furthermore, RARα and RARβ specific!agonists significantly increased proliferation in the SVZ of older animals.

All in all, we provide evidence that supports the idea that RA signalling plays a role in the regulation of adult neurogenesis. RA signalling proteins are expressed in neurogenic niches. Although RA signalling does not control the migration of neuroblasts in the adult brain, it does play a role in governing the proliferation of cells in the SVZ and DG, and in the age-related decline of adult-neurogenesis.
Date of Award2016
Original languageEnglish
Awarding Institution
  • King's College London
SupervisorJonathan Corcoran (Supervisor) & Patrick Doherty (Supervisor)

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