Two Splice Variants of the Wilms' Tumor 1 Gene Have Distinct Functions during Sex Determination and Nephron Formation

Abstract

Alternative splicing of Wt1 results in the insertion or omission of the three amino acids KTS between zinc fingers 3 and 4. In vitro experiments suggest distinct molecular functions for + and -KTS isoforms. We have generated mouse strains in which specific isoforms have been removed. Heterozygous mice with a reduction of +KTS levels develop glomerulosclerosis and represent a model for Frasier syndrome. Homozygous mutants of both strains die after birth due to kidney defects. Strikingly, mice lacking +KTS isoforms show a complete XY sex reversal due to a dramatic reduction of Sry expression levels. Our data demonstrate distinct functions for the two splice variants and place the +KTS variants as important regulators for Sry in the sex determination pathway.

Sex determination: insights from the chicken

“…There is evidence that SF1 and WT1 activate SRY expression in mammals, thereby setting the scene for testis differentiation. (53,54) In the absence of SRY, these genes must activate alternative sex determinants in the chicken and other vertebrates. In the case of WT1, differential splicing produces different proteins that have quite different regulatory functions during gonadogenesis.…”

Colocalization of WT1 and cell proliferation reveals conserved mechanisms in temperature‐dependent sex determination

“…WT1 is a zinc-finger DNA-binding protein that is essential for gonad development and sex determination in humans and mice (Hastie, 1992;Kriedberg et al, 1993;Vidal and Schedl, 2000;Hammes et al, 2001). In mammals, WT1 is localized to somatic cells in the gonad primordium of both sexes.…”

“…As in mammals, strong WT1 labeling becomes specific to particular cell types after sex determination, including the cells in the surface epithelium and the support cell lineages of both sexes, i.e., Sertoli cells in the testis and pre-follicle cells in the ovary. In mammals, a specific isoform of WT1 is essential for normal levels of expression of the male sex-determining gene (Sry) and the development of the testis pathway (Klamt et al, 1998;Hammes et al, 2001). Interestingly, the region that gives rise to this isoform is conserved in all vertebrate WT1 sequences yet examined and WT1 RNA with and without this region is expressed in the turtle urogenital ridge during the temperature-sensitive period .…”

La différenciation du sexe

“…L'invalidation de ces gènes chez la souris n'a d'effet qu'à l'état homozygote : en l'absence de Wt1 les animaux présentent une absence de rein, de surrénales et de gonades dans les deux sexes, et en l'absence de Sox9 une létalité embryonnaire en milieu de gestation [8,22]. Dans les deux cas, des stratégies d'invalidation conditionnelle (Sox9) ou de certaines isoformes (Wt1) ont du être développées afin d'appréhender le rôle de ces gènes dans la gonadogenèse [23,24]. Un autre exemple est celui du gène DMRT1 impliqué dans un phé-notype d'inversion sexuelle de type femme XY chez des patients .…”