Birth of fertile bimaternal offspring following intracytoplasmic injection of parthenogenetic haploid embryonic stem cells

Li, Zhikun; Wang, Haifeng; Feng, Guihai; Wang, Leyun; He, Zhengquan; Wang, Yukai; Wang, Xiu‐Jie; Li, Wei; Zhou, Qi; Hu, Baoyang

doi:10.1038/cr.2015.151

Cited by 46 publications

(39 citation statements)

References 13 publications

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“…Whether sperm RNAs are necessary for early embryonic development remains controversial 129–131 , particularly given the recent generation of parthenogenetic mice with appreciable survival rates 132,133 ; nonetheless, their potential synergistic action with maternal RNAs have been discussed with interest 134 . Thus far, the most significant biological functions identified for sperm RNAs are their involvement in non-Mendelian inheritance in mammals, such as the paramutation phenomenon in mice (BOX 2), and their contribution to the intergenerational inheritance of paternally acquired traits, including mental and nutritional stresses 9,24–26 .…”

Section: Figurementioning

confidence: 99%

Epigenetic inheritance of acquired traits through sperm RNAs and sperm RNA modifications

2016

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Once deemed heretical, emerging evidence now supports the notion that the inheritance of acquired characteristics can occur through ancestral exposures or experiences and that certain paternally acquired traits can be ‘memorized’ in the sperm as epigenetic information. The search for epigenetic factors in mammalian sperm that transmit acquired phenotypes has recently focused on RNAs and, more recently, RNA modifications. Here, we review insights that have been gained from studying sperm RNAs and RNA modifications, and their roles in influencing offspring phenotypes. We discuss the possible mechanisms by which sperm become acquisitive following environmental–somatic–germline interactions, and how they transmit paternally acquired phenotypes by shaping early embryonic development.

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Section: Figurementioning

confidence: 99%

Epigenetic inheritance of acquired traits through sperm RNAs and sperm RNA modifications

2016

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“…Previously, using homologous recombination, we introduced two deleted regions in phESCs and produced bimaternal mice (referred to as 2KO-bimaternal mice) by injection into MII oocytes (Figure 2A; Li et al, 2016). The cells were used after prolonged in vitro cultivation ($40 passages) and were expected to display the PGC-like hypomethylation status.…”

Section: Production Of Normal Bimaternal Mice With Hypomethylated Phescsmentioning

confidence: 99%

“…Haploid embryonic stem cells (haESCs) have been successfully generated in mice, rats, monkeys, and humans (Leeb and Wutz, 2011;Li et al, 2014;Sagi et al, 2016;Yang et al, 2013) and have provided new platforms for genetic screening and animal production (Li et al, , 2014Sagi et al, 2016;Yang et al, 2012). Previously, we produced bimaternal mice by injecting parthenogenetic haploid ESCs (phESCs) with deletions of the H19 and Dlk-Dio2 intergenic region (IG) imprinted regions into MII oocytes and demonstrated the indispensability of the IG deletion (Li et al, 2016). By further characterization of haploid ESCs, we aim to determine why some deletions are sufficient to cross bimaternal reproduction barriers in mammals.…”

Section: Introductionmentioning

confidence: 99%

Generation of Bimaternal and Bipaternal Mice from Hypomethylated Haploid ESCs with Imprinting Region Deletions

Wang

et al. 2018

Cell Stem Cell

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Graphical Abstract Highlights d Haploid ESCs display PGC-like methylation profiles following in vitro cultivation d Parthenogenetic and androgenetic haploid ESCs show different demethylation dynamics d phESCs carrying 3 deleted imprinted regions support normal growth of bimaternal mice d ahESCs carrying 7 deleted imprinted regions produce live full-term bipaternal mice SUMMARYUnisexual reproduction is widespread among lower vertebrates, but not in mammals. Deletion of the H19 imprinted region in immature oocytes produced bimaternal mice with defective growth; however, bipaternal reproduction has not been previously achieved in mammals. We found that cultured parthenogenetic and androgenetic haploid embryonic stem cells (haESCs) display DNA hypomethylation resembling that of primordial germ cells. Through MII oocyte injection or sperm coinjection with hypomethylated haploid ESCs carrying specific imprinted region deletions, we obtained live bimaternal and bipaternal mice. Deletion of 3 imprinted regions in parthenogenetic haploid ESCs restored normal growth of fertile bimaternal mice, whereas deletion of 7 imprinted regions in androgenetic haploid ESCs enabled production of live bipaternal mice that died shortly after birth. Phenotypic analyses of organ and body size of these mice support the genetic conflict theory of genomic imprinting. Taken together, our results highlight the factors necessary for crossing same-sex reproduction barriers in mammals.

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“…reported that parthenogenetic haploid embryonic stem cells derived from a single oocyte contained only one set of the maternal genome, and the imprinting gene expression was different from each other (Li et al . ; Zhong et al . ).…”

Section: Discussionmentioning

confidence: 99%

Embryos aggregation improves development and imprinting gene expression in mouse parthenogenesis

et al. 2016

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Mouse parthenogenetic embryonic stem cells (PgESCs) could be applied to study imprinting genes and are used in cell therapy. Our previous study found that stem cells established by aggregation of two parthenogenetic embryos at 8-cell stage (named as a 2 PgESCs) had a higher efficiency than that of PgESCs, and the paternal expressed imprinting genes were observably upregulated. Therefore, we propose that increasing the number of parthenogenetic embryos in aggregation may improve the development of parthenogenetic mouse and imprinting gene expression of PgESCs. To verify this hypothesis, we aggregated four embryos together at the 4-cell stage and cultured to the blastocyst stage (named as 4aPgB). qPCR detection showed that the expression of imprinting genes Igf2, Mest, Snrpn, Igf2r, H19, Gtl2 in 4aPgB were more similar to that of fertilized blastocyst (named as fB) compared to 2aPgB (derived from two 4-cell stage parthenogenetic embryos aggregation) or PgB (single parthenogenetic blastocyst). Post-implantation development of 4aPgB extended to 11 days of gestation. The establishment efficiency of GFP-a 4 PgESCs which derived from GFP-4aPgB is 62.5%. Moreover, expression of imprinting genes Igf2, Mest, Snrpn, notably downregulated and approached the level of that in fertilized embryonic stem cells (fESCs). In addition, we acquired a 13.5-day fetus totally derived from GFP-a 4 PgESCs with germline contribution by 8-cell under zona pellucida (ZP) injection. In conclusion, four embryos aggregation improves parthenogenetic development, and compensates imprinting genes expression in PgESCs. It implied that a 4 PgESCs could serve as a better scientific model applied in translational medicine and imprinting gene study.

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Birth of fertile bimaternal offspring following intracytoplasmic injection of parthenogenetic haploid embryonic stem cells

Cited by 46 publications

References 13 publications

Epigenetic inheritance of acquired traits through sperm RNAs and sperm RNA modifications

Epigenetic inheritance of acquired traits through sperm RNAs and sperm RNA modifications

Generation of Bimaternal and Bipaternal Mice from Hypomethylated Haploid ESCs with Imprinting Region Deletions

Embryos aggregation improves development and imprinting gene expression in mouse parthenogenesis

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