Wilms Tumor Gene 1: Lessons from Kidney Development and Cancer

Am J Physiol Renal Physiol. 2023 Nov 2. doi: 10.1152/ajprenal.00248.2023. Online ahead of print.ABSTRACTIn 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 ...
Source: American Journal of Physiology. Renal Physiology - Category: Physiology Authors: Source Type: research