Birth of parthenogenetic mice that can develop to adulthood

Abstract

Only mammals have relinquished parthenogenesis, a means of producing descendants solely from maternal germ cells. Mouse parthenogenetic embryos die by day 10 of gestation. Bi-parental reproduction is necessary because of parent-specific epigenetic modification of the genome during gametogenesis. This leads to unequal expression of imprinted genes from the maternal and paternal alleles. However, there is no direct evidence that genomic imprinting is the only barrier to parthenogenetic development. Here we show the development of a viable parthenogenetic mouse individual from a reconstructed oocyte containing two haploid sets of maternal genome, derived from non-growing and fully grown oocytes. This development was made possible by the appropriate expression of the Igf2 and H19 genes with other imprinted genes, using mutant mice with a 13-kilobase deletion in the H19 gene as non-growing oocytes donors. This full-term development is associated with a marked reduction in aberrantly expressed genes. The parthenote developed to adulthood with the ability to reproduce offspring. These results suggest that paternal imprinting prevents parthenogenesis, ensuring that the paternal contribution is obligatory for the descendant.

Epigenetics and neural stem cell commitment

“…This permits the downstream enhancers freely interact with Igf2, resulting in Igf2 expression from the paternal chromosome [32] . In addition, the methylated DMD also acts as the silencer to repress the transcription of the paernal H19 allele.Kono et al strongly demonstrated that H19 played a crucial role in development [33] and cis-regulation of Igf2 expresstion. Additionally, the abnormality of H19-IGF2 imprinting is linked to tumorigenesis.…”

“…Kono et al strongly demonstrated that H19 played a crucial role in development [33] and cis-regulation of Igf2 expresstion. Additionally, the abnormality of H19-IGF2 imprinting is linked to tumorigenesis.…”

The DLK1-MEG3 locus in malignant cells of proposed primordial germ cell origins.

“…Though the exact mechanism of genomic imprinting for this locus is not yet fully described, the importance of the ICR for gene transcription was previously shown in a seminal paper by Kono, et al, in which bimaternal mice were generated for the first time via manipulation of only the Igf2-H19 locus [15]. Gametes carry specific chemical modifications to their chromatin, including DMR methylation and posttranslational modifications to histone proteins, such that the fusion of egg and sperm causes these chemical modifications to complement each other at imprinted loci.…”

“…Kono, et al found that fusing one normal oocyte with one oocyte from which the Igf2-H19 ICR and the H19 gene were deleted overcame the growth restriction which accompanied oocyte fusion and resulted in the full-term development of mice [15].…”

“…Seminal work on the generation of bimaternal mice implicated two paternally imprinted loci as key barriers to this process: IGF2-H19 and DLK1-MEG3 [15,120]. Later work determined that genetic manipulation of either locus was sufficient to carry pups through the majority of growth and development, but manipulation of both loci was necessary to efficiently create live, healthy mice [15,17,121].…”