The Wilms' tumor (WT) suppressor gene (Wt1) encodes a zinc finger nuclear transcription factor. WT1 functions in cell growth and differentiation. Congenital WT1 mutations predispose to Wilms tumor (a tumor of the kidneys), and are observed in individuals with Denys-Drash Syndrome, Frasier Syndrome and WAGR (Wilms tumour, aniridia [absence of iris], genitourinary anomalies and retardation). A combination of germline and somatic mutations are observed in a subset of Wilms tumor where they are almost invariably homozygous - resulting in inactivation of WT1. Somatic WT1 mutations are present in acute and chronic myeloid leukemia, myelodysplastic syndrome and other blood neoplasms (including acute lymphoblastic leukemia). Wilms tumors display WT1 expression similar to fetal kidney, consistent with the fetal origin of Wilms tumors.
In mice, germline knockout of WT1 (Wt1-/-) results in apoptosis of intermediate mesoderm and subsequent failure of kidney and gonadal development. Wt1-/- embryos die during fetal development or at birth, depending upon strain background. Somatic mosaic inactivation of Wt1 results in the development of Wilms tumor in the background of biallelic expression of the normally imprinted Igf2 gene
The Wt1 floxed allele (Wt1flox) has loxP sites flanking Wt1 exons 8-9 (encoding the second and third of the four DNA-binding zinc-finger domains). Mice homozygous for this floxed allele (Wt1flox/flox) are viable and fertile with no reported gross physical or behavioral abnormalities. The donating investigator reports that homozygotes have normal expression levels of WT1 mRNA and protein.
When bred to mice that express Cre recombinase, the resulting offspring will have the floxed region deleted in cre-expressing tissues. The deletion allele (Wt1Δ) encodes an in-frame truncated protein that is expressed at levels similar to endogenous WT1, but the Wt1Δ protein is non-functional. Homozygous deletion (Wt1Δ/Δ) embryos are phenotypically like Wt1-/- embryos - consistent with Wt1Δ being a loss-of-function allele.
