Maternal Cripto is critical for proper development of the mouse placenta and the placental vasculature

The growth and survival of the mammalian fetus is highly dependent on the placenta. Several research groups have demonstrated the involvement of different transforming growth factor-beta (TGFβ) superfamily members and their related receptors in placentation. Cripto is a member of the epidermal growth factor-Cripto1/FRL1/Cryptic protein family and plays a critical role in embryonic development, stem cell maintenance and tumor progression through TGFβ-dependent and independent pathways. Several studies have suggested that Cripto may also have a role in female reproduction and pregnancy maintenance, but its specific role remains elusive.

We used a conditional knockout mouse model in which Cripto is deleted from the uterus using a loxP-Cre system. Cripto cKO females were mated with wildtype males and dissections were performed at different timepoints during pregnancy for assessment of the number and size of the implantation sites, resorption sites, fetal weight and placental development. Histology, IF staining and quantitative PCR were employed to analyze the placentation process.

We found that loss of maternal Cripto results in defective placentation, decreased vascularization within the placental labyrinth and leads to intrauterine growth restriction and fetal death. We further demonstrated that components of the VEGF and Notch signaling pathways are downregulated in Cripto cKO decidua and placenta potentially contributing to defects in the development of the vasculature at maternal-fetal interface.

These findings demonstrate that maternal Cripto is involved in the maternal-fetal communications required for proper development of the placenta and placental vasculature.