Loss of Slc38a4 imprinting is a major cause of mouse placenta hyperplasia in somatic cell nuclear transferred embryos at late gestation

Placenta hyperplasia is commonly observed in cloned animals and is believed to impede the proper development of cloned embryos. However, the mechanism underlying this phenomenon is largely unknown. Here, we show that placenta hyperplasia of cloned mouse embryos occurs in both middle and late gestation. Interestingly, restoring paternal-specific expression of an amino acid transporter Slc38a4, which loses maternal H3K27me3-dependent imprinting and becomes biallelically expressed in cloned placentae, rescues the overgrowth of cloned placentae at late gestation. Molecular analyses reveal that loss of Slc38a4 imprinting leads to over-activation of the mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway in cloned placentae, which is likely due to the increased amino acids transport by SLC38A4. Collectively, our study not only reveals loss of Slc38a4 imprinting is responsible for overgrowth of cloned placentae at late gestation but also suggests the underlying mechanism involves increased amino acid transport and over-activation of mTORC1.

Automated summary

Placenta hyperplasia is a common issue in cloned animals and negatively affects the development of cloned embryos. The underlying mechanism behind this phenomenon is largely unknown. In this study, the authors found that placenta hyperplasia occurs in both middle and late gestation in cloned mouse embryos. They further discovered that restoring the expression of a specific amino acid transporter, Slc38a4, can rescue the overgrowth of cloned placentae in late gestation. Molecular analyses revealed that loss of Slc38a4 imprinting leads to over-activation of the mTORC1 signaling pathway, likely due to increased amino acid transport. The findings suggest that loss of Slc38a4 imprinting is responsible for the overgrowth of cloned placentae, and the underlying mechanism involves increased amino acid transport and over-activation of mTORC1.