Regulated expression of two sets of paternally imprinted genes is necessary for mouse parthenogenetic development to term

Abstract

Mouse parthenogenetic embryos (PEs) are developmentally arrested until embryo day (E) 9.5 because of genomic imprinting. However, we have shown that embryos containing genomes from non-growing (ng) and fully grown (fg) oocytes, i.e. ngwt/fgwtPE (wt, wild type), developed to E13.5. Moreover, parthenogenetic development could be extended to term by further regulation ofIgf2andH19expression using mice with deletion of theH19transcription unit (H19Δ13) together with its differentially unit (DMR). To gain an insight into the extended development of the parthenotes to term, we have here investigated the expression levels of paternally imprinted genes in ngH19Δ13/fgwtPE throughout their development. In ngH19Δ13/fgwtPes that died soon after recovery, the expression ofIgf2andH19was restored to the appropriate levels except for lowIgf2expression in the liver after E15.5. Further, the paternally expressedDlk1andDio3were repressed, while the expression levels of the maternalGtl2andMirgwere twice those of the controls. However, the above-mentioned four genes showed almost normal expression in the surviving ngH19Δ13/fgwtPEs. The methylation analysis revealed that the intragenic DMR of theDlk1-Gtl2domain was hypermethylated in the ngH19Δ13/fgwtPEs that survived, but not in the PEs that died soon after recovery. The present study suggests that two sets of co-ordinately regulated but oppositely expressed genes,Igf2-H19andDlk1-Gtl2,act as a critical barrier to parthenogenetic development in order to render a paternal contribution obligatory for descendants in mammals.