Multiple roles for the Wilms' tumor suppressor, WT1

Wilms' tumor Is a childhood kidney tumor that is a striking example of the way that cancer may arise through development gone awry, A proportion of th ese tumors develop as a result of the loss of function mutations in the Wil ms' tumor suppressor gene, WT1. Inherited mutations in the WT1 gene can lea d to childhood kidney cancer, severe gonadal dysplasia, and life-threatenin g hypertension. Knockouts show that the gene is essential for the early sta ges of kidney and gonad formation. These tissues are completely absent in n ull mice. The WT1 gene encodes numerous protein isoforms, all of which shar e four zinc fingers. There is a large body of evidence supporting the notio n that WT1 is a transcription factor, particularly a transcriptional repres sor, Recently, however, we obtained evidence that WT1 colocalizes and is ph ysically associated with splice factors. What is more, one alternative spli ce isoform of WT1 containing three amino acids, Lys-Thr-Ser (KTS; inserted between zinc fingers 3 and it) is preferentially associated with splice fac tors, whereas the other alternative splice version, lacking these three ami no acids, preferentially associates with the transcriptional apparatus, Bot h genetic and evolutionary considerations suggest that these two different forms of the protein have different functions. We will discuss recent evide nce to further implicate WT1 in splicing. Our results raise the possibility that regulation of splicing is a crucial factor in the development of the genitourinary system, and that tumors may arise through aberrant splicing, To pursue the regulation and function of WT1 in whole animals, we have been introducing the human gene and large flanking regions cloned in yeast arti ficial chromosomes directly into mice. These studies have allowed us to dis sect the function of WT1 at late as well as at early stages in organogenesi s and to identify new sites and surprising new potential functions for the gene.