The tumour suppressor gene WT1 encodes a transcription factor expressed in tissues of the genito-urinary system. Inactivation of this gene is associated with the development of Wilms tumour a pediatric kidney cancer. We show that WT1 is also expressed at high levels in many supportive structures of mesodermal origin in the mouse. We also describe a case of adult human mesothelioma, a tumour derived from the peritoneal lining, that contains a homozygous point mutation within WT1. This mutation, within the putative transactivation domain, converts the protein from a transcriptional repressor of its target sequence to a transcriptional activator. The role of WT1 in normal development thus extends to diverse structures derived from embryonic mesoderm and disruption of WT1 function contributes to the onset of adult, as well as pediatric, tumours.

Nephrogenic rests consist of foci of primitive renal cells, typically microscopic, that are found within the normal kidney tissue of children with Wilms' tumour. To study the relationship between nephrogenic rests and the associated tumours, we screened these lesions for mutations in the 11p13 Wilms' tumour suppressor gene, WT1. In two cases in which the Wilms' tumour contained a somatic WT1 mutation, the nephrogenic rest had the identical mutation. Nephrogenic rests and Wilms' tumours are therefore topographically distinct lesions that are clonally derived from an early renal stem cell. Inactivation of WT1 appears to be an early genetic event which can lead to the formation of nephrogenic rests, enhancing the probability that additional genetic hits will lead to Wilms' tumour.

SummaryThe full neutrophil heterogeneity and differentiation landscape remains incompletely characterized. Here we profiled >25,000 differentiating and mature mouse neutrophils using single-cell RNA sequencing to provide a comprehensive transcriptional landscape of neutrophil maturation, function, and fate decision in their steady state and during bacterial infection. Eight neutrophil populations were defined by distinct molecular signatures. The three mature peripheral blood neutrophil subsets arise from distinct maturing bone marrow neutrophil subsets. Driven by both known and uncharacterized transcription factors, neutrophils gradually acquire microbicidal capability as they traverse the transcriptional landscape, representing an evolved mechanism for fine-tuned regulation of an effective but balanced neutrophil response. Bacterial infection reprograms the genetic architecture of neutrophil populations, alters dynamic transition between each subpopulation, and primes neutrophils for augmented functionality without affecting overall heterogeneity. In summary, these data establish a reference model and general framework for studying neutrophil-related disease mechanisms, biomarkers, and therapeutic targets at single-cell resolution.Graphical AbstractHighlightsA comprehensive single-cell resolution transcriptional landscape of mouse neutrophil maturation and fate decision under steady-state and bacterial infection conditions.The pathogen clearance machinery in neutrophils is continuously and gradually built during neutrophil differentiation, maturation, and aging, driven by both known and uncharacterized transcription factors.The three mature neutrophil subsets in peripheral blood, including a novel ISG-expressing subset, are derived from distinct bone marrow neutrophil precursors.Bacterial infection reprograms the genetic architecture of neutrophil populations, alters dynamic transition between each subpopulation, and primes neutrophils for augmented functionality without affecting overall neutrophil heterogeneity.Bacterial infection-induced emergency granulopoiesis is mediated by augmented proliferation of early stage neutrophil progenitors and accelerated post-mitotic maturation.