Seminars in Cell & Developmental Biology 14 (2003) 233–240 WT1 and glomerular function A.L. Menke a,* , A. Schedl b,1 a Central Haematology Laboratory, University Medical Centre St. Radboud, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands b INSERM U 470, Institute de Biochimie, Parc Valrose, 06108 Nice Cedex 2, France Abstract The Wilms’ Tumour 1 (WT1) gene plays an important role at three different stages of kidney development. The onset of kidney formation, the progression of kidney formation and the maintenance of normal kidney function. Disruption of WT1 may lead to a whole spectrum of kidney diseases ranging from tumour development to mild forms of renal failure. However, the underlying mechanisms are largely unknown. The WT1 proteins have been implicated in various cellular processes like proliferation, differentiation and apoptosis and in agreement with these diverse functions, the number of target genes is still mounting. The development of mouse models in recent years has contributed considerably to a better understanding of the biological activities of WT1, and in this article we will discuss the role of WT1 during kidney formation and kidney function. © 2003 Elsevier Science Ltd. All rights reserved. Keywords: Glomerular sclerosis; Podocyte; Wilms’ tumour; WT1; Renal failure 1. The Wilms’ Tumour 1 (WT1) gene and its products The human WT1 gene is localised on chromosome band 11p13. It contains 10 exons and spans about 50 kb [1,2] (Fig. 1). The gene mainly encodes a transcript of about 3 kb [3] but smaller transcripts have been reported as well. Trans- lation of the WT1 transcript reveals a protein that contains four zinc fingers of the Kruppel C2–H2 class in the carboxyl terminus and which has a proline/glutamine-rich amino ter- minus. As a result of alternative RNA splicing, each transcript can encode for four different proteins [4] with molecular weights of 52–54 kDa [5]. One alternative splicing event results in ei- ther inclusion or exclusion of exon 5, which encodes a stretch of 17 amino acids (±17 aa) just N-terminal of the four zinc fingers. The other event involves a selection of alternative splice acceptor sites in exon 9, resulting in the presence or absence of a three amino acid insert (lysine-threonine-serine [±KTS]) between zinc fingers three and four. Recently, alternative translational initiation sites have been found upstream [6] and downstream [7] of the major AUG trans- lational initiation site, resulting in WT1 proteins with re- spectively higher (60–62 kDa) and lower molecular weights * Corresponding author. Tel.: +31-24-361-0401; fax: +31-24-361-0373. E-mail addresses: a.menke@chl.umcn.nl (A.L. Menke), schedl@unice.fr (A. Schedl). 1 Tel.: +33-492-07-64-53 (lab)/+33-492-07-64-01 (office); fax: +33-492-07-64-02. (36–38 kDa). RNA editing may also occur leading to the re- placement of a leucine by a proline at position 281 [8]. Alto- gether there may be as many as 24 different WT1 isoforms. Since the predicted protein sequence suggested the WT1 isoforms to be transcription factors, several studies focused on identifying their target genes. So far, more than 40 puta- tive WT1-target genes have been identified but their physio- logical significance remains to be elucidated (Table 1). The WT1 isoforms may also function as co-factors, ex- erting their effect on transcriptional regulation by binding to other proteins like SF1 [9], hsp70 [10], or CBP [11] and some of the WT1 isoforms may be involved in the regula- tion of RNA splicing [12]. 2. WT1 and normal kidney development The kidney is formed through the reciprocal interaction of two tissues; the metanephric mesenchyme and the ep- ithelium of the ureteric bud [13]. Around E35 in humans and E11 in mice, the metanephric mesenchyme induces the Wolffian duct. As a result, the ureteric bud evaginates from the caudal end of the Wolffian duct, invades the metanephric mesenchyme and branches. Upon induction by the ureteric bud, the mesenchymal cells undergo a burst of prolifera- tion, followed by aggregation and subsequent formation of the blastema around the ureteric bud (Fig. 2). The blastema develops into the renal vesicle and matures further via the comma- and S-shaped bodies into epithelial cells that form 1084-9521/$ – see front matter © 2003 Elsevier Science Ltd. All rights reserved. doi:10.1016/S1084-9521(03)00026-0