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For more than three 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 posttranscriptional 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 the 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\u2013Drash syndrome, Frasier syndrome, and WAGR syndrome. Although the WT1 story began with Wilms\u2019 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 premalignant clones with inadequate DNA repair enzymes and may disturb the epigenetic landscape. Yet none of these observations provide a complete picture of Wilms\u2019 tumor pathogenesis. It appears that the WT1 odyssey is unfinished and still holds a great deal of untilled ground to be explored. <\/jats:p>","DOI":"10.1152\/ajprenal.00248.2023","type":"journal-article","created":{"date-parts":[[2023,11,2]],"date-time":"2023-11-02T08:00:41Z","timestamp":1698912041000},"page":"F3-F19","update-policy":"https:\/\/doi.org\/10.1152\/aps-crossmark-policy","source":"Crossref","is-referenced-by-count":22,"title":["Wilms\u2019 tumor gene 1: lessons from the interface between kidney development and cancer"],"prefix":"10.1152","volume":"326","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9836-8246","authenticated-orcid":false,"given":"Elena","family":"Torban","sequence":"first","affiliation":[{"name":"Department of Medicine, McGill University and Research Institute of McGill University Health Center, Montreal, Quebec, 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