The role of Neogenin during neurogenesis and migration in the embryonic forebrain

Stacey Cole (2010). The role of Neogenin during neurogenesis and migration in the embryonic forebrain PhD Thesis, Queensland Brain Institute, The University of Queensland.

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Author Stacey Cole
Thesis Title The role of Neogenin during neurogenesis and migration in the embryonic forebrain
School, Centre or Institute Queensland Brain Institute
Institution The University of Queensland
Publication date 2010-01
Thesis type PhD Thesis
Supervisor Associate Professor Helen Cooper
Total pages 179
Total colour pages 46
Total black and white pages 133
Subjects 11 Medical and Health Sciences
Abstract/Summary The proliferation and differentiation of neural progenitors during neurogenesis, and their subsequent migration and positioning within the embryonic forebrain, are key processes of cortical development. The neuronal progenitors of the cortex are the radial glia, which give rise to pyramidal neurons that then migrate towards the outer surface. In the ventral forebrain, progenitors give rise to interneurons that migrate tangentially into the developing cortex and integrate into the circuitry of the brain. Abnormal neuronal migration is the underlying cause of several human disorders, including lissencephaly and epilepsy. Neogenin is a member of the immunoglobulin (Ig) superfamily and is closely related to the axon guidance receptor Deleted in Colorectal Cancer (DCC). Neogenin has been identified as a receptor for members of the Netrin and Repulsive Guidance Molecule (RGM) ligand families, and has been shown to regulate a range of developmental processes including axon guidance, neural tube closure, and mammary gland development. In this thesis we investigate the role of Neogenin during development of the mouse forebrain. The precise mRNA expression and protein localisation patterns of Neogenin in the developing forebrain are described, with Neogenin detected in both progenitor and neuronal populations. We also characterise the Neogenin (Neo1Gt) loss-of-function mouse, where it was shown that the Neogenin mutation in these animals was hypomorphic, with full-length protein detected in embryonic mice homozygous for the mutation. As a result, we determined that these animals displayed variable phenotypic defects with low penetrance in the developing forebrain. It was also shown that Neogenin played a role in neuronal differentiation. In vitro, Neogenin regulated interneuron differentiation in the presence of RGMa, a ligand for Neogenin, with an increase in interneuron number when cells were cultured in the presence of high levels of the ligand. Furthermore, this thesis also demonstrated that RGMa was involved in the regulation of neurite outgrowth in neuronal cultures. Finally, using an explant assay this study demonstrated that RGMa induced a chemorepulsive response in interneurons migrating from the medial ganglionic eminences. This suggests that Neogenin plays a role in interneuron migration in the ventral forebrain. To determine the precise role of Neogenin during neurogenesis and migration, further work utilising siRNA Neogenin knockdown in an optimised lentivirus system would be required. This would confirm a role for Neogenin in neuronal differentiation, migration and neurite outgrowth in the developing mammalian forebrain.
Keyword Neogenin, Netrin, RGM, neurogenesis, interneuron, tangential migration, differentiation
Additional Notes 17, 19, 20, 24, 28, 33, 46, 49, 51, 53-55, 57, 59, 61, 62, 65, 67-69, 75-78, 82, 85, 87, 89, 91, 102, 103, 109, 111, 113, 114, 116, 120, 123, 127, 129, 133, 135, 136, 140, 149, 150

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Created: Wed, 13 Oct 2010, 10:01:52 EST by Stacey Cole on behalf of Library - Information Access Service