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Wilms' Tumor Suppressor Gene WT1: from Structure to Renal

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Wilms' Tumor Suppressor Gene WT1: from Structure to Renal J Am Soc Nephrol 11: S106–S115, 2000 Wilms’ Tumor Suppressor Gene WT1: From Structure to Renal Pathophysiologic Features CHRISTIAN MROWKA*† and ANDREAS SCHEDL* *Max Delbru¨ck Center for Molecular Medicine and †Franz Volhard Clinic, Humboldt University of Berlin, Berlin-Buch, Germany. Abstract. Normal development of the kidney is a highly com- current understanding of the structural features of WT1, how plex process that requires precise orchestration of proliferation, they modulate the transcriptional and post-transcriptional ac- differentiation, and apoptosis. In the past few years, a number tivities of the protein, and how mutations affecting individual of genes that regulate these processes, and hence play pivotal isoforms can lead to diseased kidneys is summarized. In addi- roles in kidney development, have been identified. The Wilms’ tion, results from transgenic experiments, which have yielded tumor suppressor gene WT1 has been shown to be one of these important findings regarding the function of WT1 in vivo, are essential regulators of kidney development, and mutations in discussed. Finally, data on the unusual feature of RNA editing this gene result in the formation of tumors and developmental of WT1 transcripts are presented, and the relevance of RNA abnormalities such as the Denys-Drash and Frasier syndromes. editing for the normal functioning of the WT1 protein in the A fascinating aspect of the WT1 gene is the multitude of kidney is discussed. isoforms produced from its genomic locus. In this review, our The kidney is crucial for survival. The molecular mechanisms Structural Features underlying the development of this organ, however, are only The human WT1 gene spans approximately 50 kb and in- beginning to be elucidated. Three sets of kidneys develop cludes 10 exons, which generate a 3-kb mRNA (3,4). Four zinc during embryogenesis, i.e., the pronephros, the mesonephros, finger motifs in the carboxyl-terminal portion form the DNA- and the metanephros (1). The precursors of the permanent binding domain and share homology with the early growth kidney in the metanephros result from reciprocal interactions response gene 1 family, suggesting a role for the WT1 protein between the epithelial ureteric bud and the pluripotent meta- as a transcription factor (Figure 1A). Up to 24 different iso- nephric mesenchyme. The mesenchyme induces the bud to forms may result from a combination of alternative transla- grow and branch, thus forming the ureter, renal pelvis, and tional start sites, alternative RNA splicing, and RNA editing. collecting ducts. The ureteric bud induces the mesenchyme to One alternative translational start site (CTG) is located 204 bp undergo an epithelial transformation, to condense and form upstream of the major ATG site, creating an isoform with 68 (via the comma- and S-shaped bodies) the mature nephron with additional amino acids at its amino terminus (5). Recently, the glomerulus, proximal convoluted tubule, loop of Henle, shorter versions of WT1, resulting from translation initiation at and distal convoluted tubule. In the past decade, several genes the second in-frame ATG, have also been detected (6). Two have been identified that demonstrate spatially and temporally alternatively spliced exons are known, one inserting or exclud- distinct expression patterns during kidney development and ing exon 5, which encodes 17 amino acids, and the other lead to abnormal organ development when disrupted by gene- affecting exon 9 via insertion or exclusion of three amino acids targeting experiments (for review, see reference (2). One of [lysine-threonine-serine (KTS)] between the third and forth these genes is the Wilms’ tumor suppressor gene WT1. This zinc fingers. The ratio of splice variants is highly conserved in review focuses on structural features of and how they relate to normal fetal kidney and is maintained throughout development (7). Finally, an RNA-editing site has been identified in tran- WT1 function during kidney development. This is particularly scripts of rat and human WT1 genes, leading to the replacement relevant because we want to understand the basis of WT1 of an amino acid in exon 6 (8). A more detailed description of mutations related to human renal diseases, such as the Denys- RNA editing is provided below. Drash syndrome (DDS) and the Frasier syndrome (FS). It is now well established that WT1 can bind, via its zinc fingers, to the promoter regions of Ͼ20 putative downstream target genes (for review, see reference (9). WT1 effects on transcription can be either repressing or activating, depending Correspondence to Dr. Andreas Schedl, Max Delbru¨ck Center for Molecular on the cell type and the target gene with which WT1 interacts. Medicine, Robert-Ro¨ssle Str. 10, D-13092 Berlin-Buch, Germany. Phone: 49-30-9406-2337; Fax: 49-30-9406-2110; E-mail: [email protected] Most target genes have been identified in transfection assays, 1046-6673/1111-0106 and data should be interpreted with care, because the effects of Journal of the American Society of Nephrology chromatin or other interacting proteins are usually neglected in Copyright © 2000 by the American Society of Nephrology vitro. However, in vitro experiments have been corroborated J Am Soc Nephrol 11: S106–S115, 2000 WT1, Glomerulopathy, and RNA Editing S107 Figure 1. (A) Structural features of the Wilms’ tumor suppressor gene WT1. The schematic drawing depicts the main features of the WT1 protein and its various isoforms (numbers in parentheses refer to references). (B) Frasier syndrome (FS). The schematic drawing indicates the most common intronic mutations affecting lysine-threonine-serine (KTS) splicing. aa, amino acid; PU, proteinuria; NS, nephrotic syndrome; ESRF, end-stage renal failure. by in vivo data for an increasing number of target genes that are no-terminally shorter versions seem to lead to reduced repres- either activated or repressed by WT1. These genes include sion but increased activation potential (6). How important those for the cell surface receptor epidermal growth factor these minor products are for WT1 function in vivo remains receptor (10), the transcription factor paired-box-containing unclear. However, alternatively spliced exon 5 has been sug- gene 2 (PAX2) (11), and the growth factor insulin-like growth gested to increase the repressing effect of WT1 on some factor-2 (12) as targets downregulated by WT1. Amphiregulin, promoters (16). Interestingly, the presence of the alternative a member of the epidermal growth factor family, has been exon 5 has been found only in mammalian species (14,15), shown to be a target that can be activated by WT1 (13). indicating that it has been adopted by WT1 at a later stage in Because WT1 is expressed in so many different isoforms, evolution. which are highly conserved throughout evolution (14,15), what Increasing amounts of compelling data suggest a role for properties do the different isoforms have? The addition of a WT1 not only as a transcription factor but also as a potent 68-amino acid amino-terminal region from an alternative trans- modulator at the post-transcriptional level. WT1 is able to bind lational start site has been demonstrated to have little effect on to RNA of the insulin-like growth factor-2 gene (17). How the the transcriptional activity of the protein (5). In contrast, ami- WT1 protein interacts with RNA is still under discussion. S108 Journal of the American Society of Nephrology J Am Soc Nephrol 11: S106–S115, 2000 Although one study reported that the zinc finger region (in type has not yet been observed) and early bilateral nephrec- particular, zinc finger 1) is necessary for these protein-RNA tomy before the development of Wilms’ tumor are life-saving interactions (17), computer modeling suggests that an RNA treatments. However, a late manifestation of Wilms’ tumor recognition motif in the amino-terminal region is important after renal transplantation in a child with retrospectively sus- (18). These two regions may be equally important, with the pected DDS has been observed (26). amino-terminal region serving as a nonspecific binding domain More than 60 germline mutations (both familial and de and the zinc finger region providing sequence specificity. novo) have been described, which essentially leave the WT1 Interestingly, the distinct isoforms of WT1 seem to behave protein intact but affect the DNA-binding zinc finger domain differently, in terms of their nucleic acid-binding capacity. (27) (for review, see reference (28). Most of these mutations Whereas variants lacking the KTS sequence (ϪKTS) bind to are missense mutations within exons 8 and 9, which code for DNA sequences and can act as potent transcriptional regula- zinger finger domains 2 and 3, respectively. A mutation hot tors, KTS-containing isoforms (ϩKTS) demonstrate higher spot seems to be present at nucleotide 1180 in codon 394, affinities for RNA. The actual function of the interaction of leading to the replacement of arginine with tryptophan WT1 with RNA is still unknown; it could stabilize or destabi- (R394W). Only a few deletions, insertions, and nonsense mu- lize certain RNA forms or could be involved in post-transcrip- tations result in truncated proteins. All mutations, however, tional modifications such as RNA editing or splicing. Evidence alter the structure of the DNA-binding domain, thus changing for the latter is derived from immunocolocalization and immu- its ability to bind to both DNA and RNA. The severe pheno- noprecipitation experiments. In transfection studies,
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