Life, Sex, and WT1 Isoforms— Three Amino Acids Can Make All the Difference

generated an excellent animal model for studying the mechanisms underlying the nephropathy associated with human Frasier syndrome and Denys Drash syndrome (DDS). Previous studies in human and mouse have demonstrated that WT1 is essential for the development of kidneys and gonads. The metanephric or permanent Perhaps the biggest surprise to come from the human kidney develops through the interaction of two tissues, genome sequence is the low gene number estimate the mesonephric duct and metanephric mesenchyme, relative to expectation (International Human Genome both derivatives of the intermediate mesoderm. Induc-Sequencing Consortium, 2001; Venter et al., 2001). This tion of the metanephros in the mouse starts at around has now turned the spotlight on posttranscriptional E10.5 when a signal from the mesenchyme induces ure-events as a means for generating increased proteome teric buds to grow out of the mesonephric duct and complexity. Many genes encode multiple protein isoforms, invade the mesenchyme. Signals from the ureteric buds usually through alternative splicing but also through the then induce the metanephric mesenchyme to differenti-use of alternative promoters, alternative translational ate into epithelial cells that are the precursors of the start sites, or RNA editing. We are now faced with the nephron. Following a series of patterning and morpho-huge task of identifying the functions of all these protein genetic events, these epithelia organize into the compo-isoforms that may number several hundred thousand in nents of the nephron, the proximal and distal tubules, total. the loop of Henle and the glomerulus. Signals from the The situation is epitomized by the Wilms' tumor sup-mesenchyme on the other hand induce the buds to bifur-pressor gene, WT1 (for a recent review see Little et al., cate. Eventually, the nephron will fuse with the buds 1999). Mutations in this gene in humans may lead to the which will become the collecting ducts. WT1 is ex-eponymous childhood kidney cancer, to severe kidney pressed at low levels in the undifferentiated mesen-disease (glomerular nephropathy) or gonadal dysgene-chyme and levels increase dramatically during induc-sis, often in the form of male-female sex reversal. Stud-tion. By the time the nephron intermediate or S-shaped ies in mouse have shown that WT1 is essential for the body has formed, WT1 expression becomes restricted development of the kidneys, gonads, and several other to the region that is destined to become the visceral mesodermally derived tissues (Herzer et al., 1999; Little epithelium (podocytes) of the glomerulus. These podo-et al., 1999; Moore …