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Title: Analysis of the roles of Pax6 in development of the cerebral cortex
Author: Pearson, Helen Catherine
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2000
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Here, cellular and molecular techniques were employed to elucidate the function of Pax6 in cortical development. It has been proposed that cell division within the VZ may be either symmetric, generating two progenitor cells, or asymmetric, generating a progenitor and a migratory neuron. An analysis of progenitor cleavage orientation revealed an increase in asymmetric division in the Sey/Sey cortex. In addition, interkinetic nuclear migration during the cell cycle is disrupted. I propose that these defects are most consistent with a role for Pax6 in regulating progression through the cell cycle. DiI labelling revealed a complete absence of innervation from thalamus to cortex in the Sey homozygote which may play a role in the cortical phenotype. To address this possibility an explant system was established to study cortical migration in vitro. The analysis showed that neurons migrating from the mutant cortex show a tendency to clump together indicative of differences in their adhesive properties. These defects are not rescued by co-culture with wildtype diencephalon, suggesting that the absence of thalamocortical innervation does not contribute to the Sey/Sey cortical phenotype in vivo. On the basis of these findings I hypothesise that loss of Pax6 function results in increased cortical proliferation and altered neuronal adhesion and that these abnormalities account for gradual accumulation of neurons in the VZ during later cortical development. In order to identify molecular differences between wildtype and Sey/Sey underlying these defects, candidate gene and differential gene expression analyses were performed. The former revealed altered expression patterns of putative cell determination molecules Numb and Prox1 and cell adhesion molecules L1 and TAG1. The latter involved construction and analysis of a subtracted cDNA library from which two molecules were identified which mediate protein interactions in transcriptional complexes. Expression of these genes is absent from the Sey/Sey cortex; they therefore represent exciting candidate genes acting downstream of Pax6.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available