Wilms’ tumor gene 1: lessons from the interface between kidney development and cancer

Abstract

In 1990, mutations of the WT1 gene, encoding a transcription factor in embryonic kidney, were found in 10-15% of Wilms tumors; germline WT1 mutations were associated with hereditary syndromes involving glomerular and reproductive tract dysplasia. For >3 decades, these discoveries prompted investigators to explore the embryonic role of WT1 and the mechanisms by which loss of WT1 leads to malignant transformation. Here, we discuss how alternative splicing of WT1 generates isoforms that act in a context-specific manner to activate or repress target gene transcription. WT1 also regulates post-transcriptional regulation, alters the epigenetic landscape and activates miRNA expression. WT1 functions at multiple stages of kidney development, including the transition from resting stem cells to committed nephron progenitor, which it primes to respond to WNT9b signals from ureteric bud. Wt1 then drives nephrogenesis by activating WNT4 expression and directing the development of glomerular podocytes. We review the WT1 mutations that account for Denys-Drash, Frasier and WAGR syndromes. Although the WT1 story began with Wilms tumors, an understanding of the pathways that link aberrant kidney development to malignant transformation still has some important gaps. Loss of WT1 in nephrogenic rests may leave these pre-malignant clones with inadequate DNA repair enzymes and may disturb the epigenetic landscape. Yet none of these observations provide a complete picture of Wilms tumor pathogenesis. It appears that the WT1 odyssey is unfinished and still holds a great deal of untilled ground to be explored.

Renal Tubular Epithelium in the Development of Renal Cell Carcinoma

“…WT1's role in regulating the differentiation of nephron progenitors into renal tubular epithelial cells becomes compromised, potentially leading to improper differentiation and structural abnormalities in the renal tubules. This disturbance in the normal developmental processes orchestrated by WT1 may contribute to the invasive characteristics observed in RCC, as damaged WT1 can induce alterations in cellular differentiation, fostering an environment conducive to invasive behavior and disrupting tissue integrity [40]. Furthermore, the potential association between WT1 damage and Wilms' tumor highlights its signi cant role in pediatric kidney cancer.…”

Developmental Causes of Focal Segmental Glomerulosclerosis

“…This process will give rise to the mammalian kidney. In addition, WT1 is required for nephron progenitor cells from the MM to epithelialize into embryonic podocytes [ 29 ]. WT1 also functions as a tumor suppressor gene, and constitutional and somatic variants lead to mixed clusters of nephrogenic rests within the kidney that predispose to nephroblastoma [ 30 ].…”