| Popis: |
The construction of the brain architecture and its complex neuronal circuitry are coordinated processes. Cortical development is dependent on timely production and correct migration of neurons from proliferative regions. Cortical development involves a set of complex events which includes cell proliferation, migration and differentiation. Disruption in any of these processes can lead to cortical malformations. This thesis investigated different aspects of neuronal migration during development using the zebrafish embryo as a model. We chose to investigate three models of neuronal migration. In our first model we investigated the role of the basement membranes in neuronal development using the laminin β1 zebrafish mutant grumpy (gup). We demonstrate that laminin β1 mutants display a decrease in the width of the ventricular space, a marked reduction in size of the forebrain, and ectopic FBMNs, resembling features of cobblestone (COB) Lissencephaly. We also attempted to identify an uncharacterised gup mutation. Previous studies has implicated the hydroxymethylglutaryl co-enzyme A reductase pathway in motor neuron and oligodendrocyte precursor cell migration. In our second model, we investigated the role of the HMGCoAR pathway in forebrain development of zebrafish embryos. Our data suggests the requirement of prenylation, in particular gernaylgeranylation, downstream to the HMGCoAR pathway, is required for correct neuronal positioning and ventricular space morphogenesis in the forebrain. FE65 null mouse model has previously been shown to display defects in basement membrane assembly, neuronal migration, and patterning of the cortex, thus highlighting the importance of FE65 proteins in development. In our third model we hypothesised that FE65 maintains integrity of the basement membrane in the zebrafish, and a loss of function will disrupt neuronal development. Knockdown of FE65 using antisense oligonucleotides morpholinos display defects in neuronal specification and axonal projections in the forebrain, which can be rescued by knocking down p53, suggesting that p53 may be a downstream target of FE65 signalling. |
