Gormley, Ann Marie; (1996) Transgenic approaches to studying the development of sensory and spinal cord neurons. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Differences in gene expression and sensory modality indicate that sensory neurons of dorsal root ganglia (DRG) are of more than 20 different functional subtypes. A central role in the generation of this phenotypic diversity is played by the neurotrophin receptors, TrkA, TrkB and TrkC, but other factors are undoubtedly also involved. I have investigated the role in sensory neuron development of another receptor tyrosine kinase. Ret. The ligand for this receptor has not yet been identified. The examination of Ret-deficient mice has shown that the receptor is required for the development of the enteric and some sympathetic neurons but has not elucidated the mechanism of receptor action. It seemed possible that a study of sensory neurons, that express c-ret yet survive in Ret-deficient mice, might be informative as to how Ret influences neuronal differentiation. I have shown, using in situ hybridisation and analysis of mice expressing a reporter gene driven by the c-ret promoter, that c-ret is expressed in the DRG of neonatal mice on a subset of neurons ranging from the smallest to the largest cells, c-ret is co-expressed in 85[percent] of trkA-positive neurons, but only 20[percent] of trkB-positive neurons. Identification of its co-expression with trkC was more difficult since hybridisation signal for trkC strongly labelled a minor population of the largest neurons, but also weakly labelled a larger population of moderate to small neurons, c-ret was strongly co-expressed on many of the weakly trkC-expressing neurons, but was only weakly expressed on the large, strongly trkC-expressing neurons. In the DRG of Ret-deficient mice the pattern of trkA and trkB expression was normal. In contrast, the level of trkC expression in the cells that normally express c-ret was elevated about 10-fold. I therefore suggest that one action of Ret on sensory neurons is to down-regulate trkC expression, possibly introducing a further level of phenotypic diversity in this population. This study followed my earlier attempt to generate conditionally-immortalised sensory neuronal cell lines from transgenic mice that expressed temperature-sensitive SV40 large T antigen under the control of the Hoxb4 promoter; this construct, however, appears to cause embryonic lethality prior to E9.0 and could not be used for the purpose intended.

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