Temporal gene expression changes in the developing striatum
Jeyasingham, Ragavan A.
Huntington's disease (HD) is a neurodegenerative condition in which the predominant loss of neurons occurs in the striatum. At present there is no treatment for this condition, although neural transplantation may prove to be a viable therapeutic strategy if an appropriate source of donor cells can be identified. A major requirement of these donor cells is that they are able to differentiate into the cells lost to the disease process that is, largely medium spiny projection neurons (MSNs). Currently, suitable donor cells (i.e. those already committed to developing into MSNs) can be extracted from foetal brain and early clinical trials have provided some evidence of efficacy when human foetal-derived striatum is transplanted into the brain of patients with HD. However, there is a major problem of supply and demand with respect to human foetal tissue and so alternative source of donor cells must be identified. However, only a small proportion of animal studies in the literature report differentiation of MSNs from either animal or human stem cell sources and the percentage of mature MSNs is generally low, most cells becoming glia or taking on a 'default' GABA-ergic neuronal phenotype. Thus it is likely that stem cells will need to be 'directed' towards a MSN phenotype. Knowledge of the molecular signals that cause striatal progenitors to differentiate into a MSN phenotype in vivo would help us to understand how to direct the fate of stem cell populations towards this phenotype in vitro. In this thesis I have studied the genetic changes that occur during normal striatal development in the mouse with the aims being (i) to identify genetic markers of stages of differentiation for these cells and (ii) to identify genes important for striatal development with the ultimate aim of using this information to design protocols to direct the differentiation of stem cells towards a MSN phenotype. I have studied the gene expression of the population of cells that make up the whole ganglionic eminence during its period of peak neurogenesis using Affymetrix micro array. I then validated the results of a subset of genes that were found to be significantly up-regulated using in situ hybridisation and then used these genes to characterise either primary cells that were differentiated in vitro, or cells that have been proliferated and then differentiated in vitro. This study has not only provided a gene expression signature of a developing population of striatal precursors, enabling future experiments to compare and contrast expression patterns seen in different in vitro studies, but it has also highlighted Foxpl and Foxp2 that have been shown to have a high degree of association with this period of development. This has encouraged future work in this laboratory in which the developmental functions of these genes in relation to MSN differentiation and development will be studied.
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