Coordinate action of Wt1 and a modifier gene supports embryonic survival in the oviduct

The Wt1 gene, originally identified as a tumor suppressor gene associated w ith Wilms' tumors, encodes a zinc finger containing transcription factor ex pressed during gonadal and kidney development. Although Wt1 appears to be r equired for gonadal and kidney development, no reproductive defects were ob served in outbred females heterozygous for a targeted mutation in Wt1. In c ontrast, no litters were obtained from Wt1 +/- females on a strain 129/Sv i nbred genetic background. Ovaries were smaller in Wt1 +/- 129/Sv mice and p roduced fewer ova, but transplanted Wt1 +/- ovaries from 129/Sv females wer e able to support successful pregnancies. The inability of Wt1 +/- 129/Sv f emales to produce successful implantations after ovulation and fertilizatio n appeared to be due to the failure of one-cell embryos to undergo mitosis, such that they were lost in the oviduct before reaching the uterus. Approx imately 50% of Wt1 +/- females generated from a backcross of Wt1 +/- 129/Sv :C57Bl/6 F1 hybrids to 129/Sv were fertile, indicating the presence of a Wt 1 modifier gene that affects survival of the preimplantation embryo. Neithe r levels of WT1 protein nor the ratio of WT1 spice forms were significantly altered in Wt1 +/- reproductive organs, suggesting that this modifier effe ct acts downstream of WT1. Wt1 is therefore among a small subset of genes r equired for survival of the pre-implantation embryo, and appears to functio n non-autonomously. (C) 1999 Wiley-Liss. Inc.