WT1 regulates expression of DNA repair gene during nephrogenesis.

Mammalian nephrons arise from a population of nephron progenitor cells (NPCs) expressing the master transcription factor Wilms tumor-1 (WT1), which is crucial for NPC proliferation, migration, and differentiation. In humans, biallelic loss of precludes nephrogenesis and leads to the formation of Wilms tumor precursor lesions. We hypothesize that WT1 normally primes the NPC for nephrogenesis by inducing expression of NPC-specific DNA repair genes that protect the genome. We analyzed transcript levels for a panel of DNA repair genes in embryonic day 17.5 (E17.5) versus adult mouse kidneys and noted seven genes that were increased >20-fold. We then isolated NPCs from E17.5 kidneys and found that only one gene, nei-like DNA glycosylase 3 (), was enriched. RNAscope in situ hybridization of E17.5 mouse kidneys showed increased expression in the nephrogenic zone versus mature nephron structures. To determine whether expression is WT1 dependent, we knocked down in NPCs (60% knockdown efficiency) and noted a 58% reduction in transcript levels. We showed that WT1 interacts with the promoter and that activity of a promoter-reporter vector was increased twofold in WT1 versus WT1 cells. We propose that is a WT1-dependent DNA repair gene expressed at high levels in NPCs, where it repairs mutational injury to the genome during nephrogenesis. NEIL3 is likely just one of many such lineage-specific repair mechanisms that respond to genomic injury during kidney development. We studied the molecular events leading to Wilms tumors as a model for the repair of genomic injury. Specifically, we showed that WT1 activates DNA repair gene in nephron progenitor cells. However, our observations offer a much broader principle, demonstrating that the embryonic kidney invests in lineage-specific expression of DNA repair enzymes. Thus, it is conceivable that failure of these mechanisms could lead to a variety of "sporadic" congenital renal malformations and human disease.