Early Crypt Formation Defects in the Uterine Epithelia of Sox17 Heterozygous Mice.

SOX17 activity in the uterine epithelium is essential for the implantation of mouse embryos. Previously, we demonstrated that female Sox17 heterozygous mutant mice are subfertile, and 2 active copies of Sox17 are required for the proper implantation of mouse embryos. To understand which implantation step is most sensitive to the Sox17 gene dosage, we comprehensively investigated the phenotypes and RNA transcriptomes of Sox17 heterozygous mutant mice. Uterine Sox17 expression drastically changed according to estrous cycle and during early pregnancy. The highest Sox17 expression was observed during the receptive period for blastocyst implantation. Sox17 heterozygous uterine epithelia showed ectopic high-level expression of SOX9, another SOX factor that is normally expressed in the uterine gland. Three-dimensional analysis of the uterus on day 5 of pregnancy revealed no crypt formation near the healthy blastocysts in the Sox17 heterozygous uterine epithelium, suggesting that early defects in embryo homing had occurred. Global transcriptional analysis revealed that the expression of Amphiregulin (Areg), a gene encoding a heparin-binding epidermal growth factor receptor ligand, was decreased drastically in Sox17+/- uterine epithelia. These data imply that full Sox17 activity is required to promote early crypt formation through proper regulation of SOX9 and AREG expression at the implantation site.