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 with Wilms' tumors, encodes a zinc finger containing transcription factor expressed during gonadal and kidney development. Although Wt1 appears to be required for gonadal and kidney development, no reproductive defects were observed in outbred females heterozygous for a targeted mutation in Wt1. In contrast, no litters were obtained from Wt1 +/- females on a strain 129/Sv inbred genetic background. Ovaries were smaller in Wt1 +/- 129/Sv mice and produced fewer ova, but transplanted Wt1 +/- ovaries from 129/Sv females were able to support successful pregnancies. The inability of Wt1 +/- 129/Sv females to produce successful implantations after ovulation and fertilization 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. Approximately 50% of Wt1 +/- females generated from a backcross of Wt1 +/- 129/Sv:C57BI/6 F1 hybrids to 129/Sv were fertile, indicating the presence of a Wt1 modifier gene that affects survival of the preimplantation embryo. Neither levels of WT1 protein nor the ratio of WT1 spice forms were significantly altered in Wt1 +/- reproductive organs, suggesting that this modifier effect acts downstream of WT1. Wt1 is therefore among a small subset of genes required for survival of the pre-implantation embryo, and appears to function non-autonomously.