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Unformatted text preview: Introduction The idea is simple: you clone a gene, employ a variety of biochemical, cellular and genetic assays to understand its function and publish your findings in a scientific journal. You then lean back, take a deep breath and move on to your next challenge. Sometimes, however, life is much more complex and, despite the enormous effort from the scientific community, the precise function of a gene remains elusive. This seems to be at least in part the case for WT1 , a gene mutated in a proportion of embryonic kidney cancers termed Wilms tumours or nephroblastomas (Haber et al., 1990; Gessler et al., 1990), which are believed to arise from mesenchymal blastema cells that fail to differentiate into metanephric structures and continue to proliferate (Hastie, 1994). The biology of WT1 is complex and we now know that, in addition to its function as a tumour suppressor, this gene has multiple roles during development and maintenance of body function. Hence, it may not be surprising that mutations in WT1 are found in a variety of syndromes, including Denys-Drash syndrome (Pelletier et al., 1991; Patek et al., 1999), Frasier syndrome (Barbaux et al., 1997; Klamt et al., 1998), and WAGR (W ilms tumour, a niridia, g enitourinary malformations, mental r etardation) syndrome (Gessler et al., 1990). Additional studies have linked WT1 mutations to malignancies such as leukaemia (Inoue et al., 1994; Tamaki et al., 1999), desmoplastic small round cell tumours (Lae et al., 2002), breast cancer (Silberstein et al., 1997), lung cancer (Oji et al., 2002), and retinoblastoma (Wagner et al., 2002c). The complexity of WT1 action during development is also reflected on the molecular level. Post-transcriptional modifications of the Wt1 pre-mRNA lead to the production of up to 24 different isoforms, which seem to serve distinct but also overlapping cellular and developmental functions. Here, we examine the roles of these various isoforms and highlight recent advances in our understanding of WT1 function in development, focusing particularly on gonad formation and sex determination. We also draw attention to open questions, which should be addressed in future experiments. Owing to space limitations, we do not discuss WT1 function in cancer, and interested readers are referred to other more specialized reviews (e.g. Loeb and Sukumar, 2002; Scharnhorst et al., 2001). WT1 and embryonic development: an update WT1 is expressed during mammalian embryonic development in many tissues, including the urogenital system, spleen, certain areas of the brain, spinal cord, mesothelial organs, diaphragm, limb, proliferating coelomic epithelium, epicardium and subepicardial mesenchyme (Armstrong et al., 1993; Moore et al., 1998; Moore et al., 1999). Consistent with this expression pattern, targeted disruption of the Wt1 gene in mice leads to gonadal and renal agenesis, and severe heart, lung, spleen, adrenal and mesothelial abnormalities (Kreidberg et al., 1993; Herzer et al., 1999; Moore et al., 1999).et al....
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- Spring '11