The Wilms tumor suppressor gene wt1 is required for development of the spleen

The Wilms tumor suppressor gene WT1 (wt1 in mouse) is unique among tumor su ppressors because, in addition to its involvement in cancer [1,2] and vario us other diseases [3-6], it has an essential role in the development of cer tain organs. This is revealed by the phenotype of mice with inactivated wt1 alleles [7]. These animals exhibit a complete failure of kidney and gonad development as well as abnormalities of the heart and mesothelial structure s. On a C57BL/6 genetic background, wt1(-/-) animals die between day 13.5 ( E13.5) and 15.5 (E15.5) of embryonic development [7]. We report here that c rossing of the wt1 mutation onto different mouse backgrounds delayed embryo nic lethality until birth. In wt1(-/-) mice on these different genetic back grounds, we observed a dramatic failure of spleen development, in addition to the well characterized phenotypic abnormalities. The spleen anlage forme d at around E12 to E13 and involuted by the E15 stage, before the invasion of hematopoietic cells. The absence of proper spleen development in these w t1(-/-) embryos correlated with enhanced apoptosis in the primordial spleen cells. The expression of hox11, a gene that also controls development of t he spleen [8,9], was not altered by the inactivation of wt1. In situ hybrid ization revealed that the two genes are regulated independently. These find ings demonstrate that the penetrance of the wt1(-/-) phenotype depends on t he existence of one or more modifier gene(s) and that wt1 plays a pivotal r ole in the development of the spleen, thereby extending its role in organog enesis.