The role of neogenin in the adult brain: neuronal migration, differentiation and implications for adult neurogenesis

Dana Bradford (2010). The role of neogenin in the adult brain: neuronal migration, differentiation and implications for adult neurogenesis PhD Thesis, Queensland Brain Institute, The University of Queensland.

       
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Author Dana Bradford
Thesis Title The role of neogenin in the adult brain: neuronal migration, differentiation and implications for adult neurogenesis
School, Centre or Institute Queensland Brain Institute
Institution The University of Queensland
Publication date 2010-09
Thesis type PhD Thesis
Supervisor Assoc Prof Helen Cooper
Prof Brent Reynolds
Total pages 232
Total colour pages 232
Subjects 11 Medical and Health Sciences
Abstract/Summary The ability of the adult brain to produce neurons is well established. The molecular mechanisms controlling differentiation to a neural fate and those guiding migration of neurons from a proliferative zone to their final destination are still poorly understood. The largest proliferative region in the adult brain is the subventricular zone (SVZ) where cells differentiate into neuronal precursors. These new neurons migrate along the rostral migratory stream (RMS) and integrate into the neuronal circuitry of the olfactory bulb. Therefore the RMS is an ideal system in which to study neuronal differentiation and cell migration. Neogenin is a multi-functional receptor with diverse developmental roles including axon guidance, differentiation and migration. Neogenin has been shown to interact with two ligand families — Netrins, which are classic guidance cues well described in embryogenesis, and the Repulsive Guidance Molecules (RGMs) which have recently reported roles in axon guidance. This Thesis addresses the functional role of neogenin in the adult mouse forebrain and cerebellum. Defects in differentiation in neogenin loss of function mice (neogt/gt) are described and their mechanisms discussed. Neogenin is expressed on neural stem cells and progenitor cells in the SVZ. In vitro analysis of these cells showed significantly fewer neurons generated from neogt/gt mice, demonstrating a role for neogenin in neuronal differentiation. In vitro and in vivo, the subpopulation of neurons affected was found to be the adult-born calretinin-positive granule cell population. A corresponding decrease in granule cell layer density in both the olfactory bulb and cerebellum of neogt/gt mice was also observed. Further analysis suggests that RGMa is a candidate ligand for regulating this effect. Neuroblasts in the RMS also express neogenin, suggesting neogenin may have a role in cell migration along the RMS. The expression pattern of netrin-1 in the adult forebrain coupled with disrupted migration in mice heterozygous for the netrin-1 mutation indicates a potential role for netrin-1 in guiding migration in this system. Finally, preliminary studies in human forebrain tissue show the expression of neogenin and RGMa are conserved, suggesting their function is the same in human brains.
Keyword Adult, differentiation,
neogenin,
netrin,
neurogenesis,
migration,
RGMa.
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