Kidney Development, Disease and Regenerative Medicine
We use a variety of different mouse models with specific mutations, reporter alleles and conditional models to study the role of these genes in normal development and the earliest stages of Wilms’ tumour formation. Kidney organ cultures and their imaging, including time-lapse imaging of cultured kidneys, are important tools in this work. We also use these models as a source for in vitro cell culture systems which allows us to replace animals where possible and to perform experiments that require more cells than embryonic mouse kidneys can give us.
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Genetics of Wilms’ tumours and kidney development
Wilms’ tumours are childhood kidney tumours that are the direct result of loss of control of the nephron progenitor cells (NPC), the cells in the embryonic kidney that give rise to the complete nephron. Different genes have been found mutated in these tumours and a number of these are directly involved in the normal developmental control of NPCs. Therefore, by studying the effect of Wilms’ tumour mutations on normal kidney development we get understanding of the origins of the disease, and get an experimental entry into normal kidney development.
…Wilms’ tumours are childhood kidney tumours that are the direct result of loss of control of the nephron progenitor cells (NPC), the cells in the embryonic kidney that give rise to the complete nephron. Different genes have been found mutated in these tumours and a number of these are directly involved in the normal developmental control of NPCs. Therefore, by studying the effect of Wilms’ tumour mutations on normal kidney development we get understanding of the origins of the disease, and get an experimental entry into normal kidney development.
Of particular interest to our current work are WT1 and β-catenin. WT1 was the first Wilms’ tumour gene to be identified. We showed that it drives the mesenchymal to epithelial transition in NPCs at the start of nephron development, explaining how mutations in this gene can cause the tumours. Interestingly, Wilms’ tumour cases with mutations in WT1 not only show disturbed nephron development, but also the development of non-renal cell types and tissues, especially striated muscle. Using mouse models we recently showed that this muscle development is a rapid and direct effect of Wt1 loss. This suggests that WT1 has an important role in lineage specification or maintenance in the early developing kidney.
A second important Wilms’ tumour gene is CTNNB1, the gene encoding β-catenin. Like Wt1, β-catenin is directly involved in the control of NPCs. Many laboratories have study the role of β-catenin in the developing kidney. We have in the past contributed to this by showing that PI3K signalling is important for NPCs maintaining their progenitor state though cross-talk with β-catenin. In addition, we have a strong interest in canonical, β-catenin mediated, Wnt signalling in nephron patterning.
Interestingly, there is a strong overlap in Wilms’ tumour cases with WT1 and β-catenin mutations, making this a good model to study multi-step Darwinian selection in cancer.
From Wilms’ tumours to kidney development to regenerative medicine
NCs are not only the cells of origin of Wilms’ tumours, they are an important cell type for kidney regenerative medicine. We therefore hope to use the better understand of NPCs we get from studying Wilms’ tumour mutation to improve the techniques for the in vitro development of kidney tissue for therapeutic use.
Key publications
Our Team
Dr. Peter G.J. Hohenstein
Principal Investigator / Associate Professor
Karamjit Singh Dolt
Researcher
N. Solée Pop
PhD student
Jill W.C. Claassens
Research technician (PDC)
Conny M. Brouwers
Research technician (PDC)
Dr. Peter G.J. Hohenstein
Principal Investigator / Associate Professor
Karamjit Singh Dolt
Researcher
N. Solée Pop
PhD student
Jill W.C. Claassens
Research technician (PDC)
Conny M. Brouwers
Research technician (PDC)
Margot M.L. Linssen
Research technician (PDC)