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Title: Wilms' tumour gene, WT1, in the development of the mouse embryo and its kidney
Author: Armstrong, Jane F.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1993
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Wilms' tumour (WT), a renal tumour of early childhood, arises as a result of uncontrolled proliferation in the stem cells of the kidney due to an anomaly in their developmental pathway. A strong genetic element is known to be involved in its genesis, with more than one gene being implicated. The first of these, WT1, has recently been isolated and shown to be expressed in a specific pattern in both the developing human kidney and the tumour itself. The purpose of the work presented in this thesis was to examine the role that this gene plays in mouse embryogenesis, a system that lends itself to experimentation more readily than the human. Here, the expression of the mouse homologue of WT1 was examined in three complimentary systems; the developing mouse embryo, the kidney as it formed both in vivo and in vitro and finally, in a possible mouse model for WT. A comprehensive study of the expression pattern of WT1 during development was undertaken, using in situ mRNA hybridisation. Expression was first apparent in a small area of the lateral mesoderm in the 9 day embryo. Within 12 hours this had increased markedly, with both the lining of the whole coelomic cavity and the early urogenital ridge being labelled. As development proceeded, expression was initiated in a limited set of tissues which included the metanephros, the mesothelium, the gonads, the spleen, the developing body -wall musculature, the spinal cord and the brain. Expression was present in 15 day embryos but markedly reduced by 19 days with labelling being restricted to the kidney. The expression of WT1 in cultured kidney rudiments was then examined and found to be consistent with that observed in vivo. The gene was expressed at a low level in condensed mesenchyme, with a much higher level being detected in the developing renal corpuscle. Using the transfilter system of organ culture, it was shown that WT1 was expressed in the cap of condensed metanephric mesenchyme prior to induction and that this level increased after induction, a result confirmed using very early 11 day embryos. The mouse model of WT involved placing embryonic kidneys under the capsule of adult kidney or testis from 3 strains of mice, with the growths being recovered after a defined period. In contradiction of the published data, two distinct morphologies were observed, neither of which resembled classic WT. Both types of morphology were examined with WTI and antibodies to developmental markers and it was found that the degree of differentiation was considerably greater in the transplanted tissue than would be expected for WT. The results as a whole substantiate the importance of WT1 in tissue undergoing a mesenchymeto- epithelial transition, 'particularly during nephrogenesis. The functional significance of WT1 transcription in tissues outwith this group is less clear. Skeletal muscle is sometimes observed as a component of WT and it is intriguing that the gene is expressed transiently during a stage of muscle development. The data from the mouse points to a key role for WT1 in the initiation of the cascade of differentiation necessary for normal kidney development. The possible reasons for the failure of the mouse model to produce the Wilms' phenotype are discussed.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available