Deducing the stage of origin of Wilms' tumours from a developmental series of Wt1 mutants

Abstract

Wilms' tumours, paediatric kidney cancers, are the archetypal example of tumours caused through the disruption of normal development. The genetically best-defined subgroup of Wilms' tumours is the group caused by biallelic loss of the WT1 tumour suppressor gene. Here, we describe a developmental series of mouse models with conditional loss of Wt1 in different stages of nephron development before and after the mesenchymal-to-epithelial transition (MET). We demonstrate that Wt1 is essential for normal development at all kidney developmental stages under study. Comparison of genome-wide expression data from the mutant mouse models with human tumour material of mutant or wild-type WT1 datasets identified the stage of origin of human WT1-mutant tumours, and emphasizes fundamental differences between the two human tumour groups due to different developmental stages of origin.

WT1 Is Necessary for the Proliferation and Migration of Cells of Renin Lineage Following Kidney Podocyte Depletion

“…These findings are consistent with our previous reports on the importance of disruption of MET underlying the origin of Wilms' tumors ( Berry et al., 2015 , Hohenstein et al., 2015 ), the role of Wt1 in this MET programming ( Davies et al., 2004 , Essafi et al., 2011 ), and that loss of WT1 blocks MET in the cap mesenchyme ( Essafi et al., 2011 ).…”

“…WT1 is closely linked to the mesenchymal-epithelial balance in development and disease ( Miller-Hodges and Hohenstein, 2012 ), and the homeostasis of different cell types ( Ozdemir and Hohenstein, 2014 ), including the plasticity and cell fate of certain cells ( Karki et al., 2014 , Wen et al., 2016 ). WT1 drives MET at the start of nephron development ( Essafi et al., 2011 , Berry et al., 2015 ), although in the developing epicardium, WT1 controls the reverse, i.e., epithelial-to-mesenchymal transition ( Martinez-Estrada et al., 2010 ). WT1 enhances proliferation and migration in certain cell types in a context-dependent manner ( Wagner et al., 2008 , Brett et al., 2013 , Graziano et al., 2017 ).…”

Wilms' tumour 1 (WT1) in development, homeostasis and disease

“…Although tumour histology in these mice does not necessarily recapitulate that seen in humans with the same genetic alterations, tumours arising through Wt1 loss and increased IGF2 dose do express high levels of undifferentiated mesenchyme markers. Furthermore, deletion of Wt1 in the mesenchyme leads to activation of myogenic markers, providing a molecular explanation for the formation of ectopic muscle in Wilms' tumours with WT1 mutation (Berry et al, 2015). By contrast, glomerulosclerosis, for example that seen in children with DDS and Frasier syndrome, is due to abnormalities of kidney podocytesspecialised cells that form a filtration barrier with endothelial cells.…”

“…By contrast, glomerulosclerosis, for example that seen in children with DDS and Frasier syndrome, is due to abnormalities of kidney podocytesspecialised cells that form a filtration barrier with endothelial cells. It is now clear from several studies that WT1 is essential both for podocyte differentiation and podocyte maintenance throughout adult life (Moore et al, 1999;Hammes et al, 2001;Chau et al, 2011;Berry et al, 2015;Gebeshuber et al, 2013). Recent ChIPseq studies have shown that WT1 binds to the promoters and enhancers of around half the 200 podocyte-specific genes identified (Kann et al, 2015a;Lefebvre et al, 2015;Dong et al, 2015).…”

Proliferation of metanephric mesenchymal cells is inhibited by miR-743a-mediated WT1 suppression in vitro

“…WT1 exerts an important role in maintaining the self-renewal of MM cells, and the well-balanced development of the kidney (4-7). Loss of WT1 results in embryonic lethality and hypoplasia of the gonads, together with bilateral renal agenesis, which is characterized by an incomplete formation of the UB and concurrent apoptosis of the MM cells (7,8). Therefore, these findings suggested that WT1 is intrinsically required for the functioning of the MM cells, and is indispensable for the completion of the kidney developmental program (9), and consequently, further research on WT1 regulation is urgently required.…”