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.