Maternal Cripto is required for proper uterine decidualization and peri-implantation uterine remodeling

Cripto encodes for a cell surface receptor whose role in embryonic development and stem cell maintenance has been studied. Cripto mRNA and protein have been detected in the human uterus at all stages of the menstrual cycle. To date, there is not much known about Cripto's role in female reproduction. As Cripto null Knockout (KO) is embryonic lethal, we created a conditional KO (cKO) mouse model in which Cripto is deleted only in the reproductive tissues using a Cre-loxP system. Pregnancy rate and number of pups per litter were evaluated as general fertility indices. We observed a significant decrease in pregnancy rate and litter size with loss of uterine Cripto indicating that Cripto cKO females are subfertile. We showed that although the preimplantation period is normal in Cripto cKO females, 20% of cKO females fail to establish pregnancy and an additional 20% of females undergo full litter loss after implantation between day 5.5 postcoitum (d5.5pc) and d8.5pc. We showed that subfertility caused by loss of uterine Cripto is due to defects in uterine decidualization, remodeling, and luminal closure and is accompanied by significant downregulation of Bmp2, Wnt4 and several components of Notch signaling pathway which all are known to be important factors in uterine remodeling and decidualization. Our study demonstrates that Cripto is expressed in the uterus during critical stages of early pregnancy and its deletion results in subfertility due to implantation failure, impaired peri-implantation uterine remodeling and impaired uterine decidualization.