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First Report of Bipaternal Mice: Dad’s Turn to Cross the Same-sex Reproduction Barrier

Review of “Generation of Bimaternal and Bipaternal Mice from Hypomethylated Haploid ESCs with Imprinting Region Deletions” from Cell Stem Cell by Stuart P. Atkinson 

The deletion of the H19 imprinted region in immature oocytes permitted the birth of the first mouse from two mothers and highlighted the critical role of genomic imprinting in the inhibition of parthenogenesis [1]. While bipaternal reproduction (two fathers) has been demonstrated in fish [2], this feat has not been recapitulated in mammals, thereby suggesting the existence of additional imprinting reproduction barriers.

Previous studies from the laboratories of Wei Li, Qi Zhou, and Bao-Yang Hu (Chinese Academy of Sciences, Beijing, China) generated bimaternal mice via the injection of parthenogenetic haploid ESCs (phESCs) displaying low DNA methylation levels and deletions of two imprinted regions into MII oocytes [3]. However, these mice still displayed growth retardation and other abnormalities. 

Now, the team returns with a new Cell Stem Cell article in which the authors explore the links between DNA methylation, imprinting barriers, and uniparental reproduction and describe the efficient generation of healthy and fertile bimaternal mice and the first report of the generation of full-term bipaternal mice [4].

Initial analyses by Li et al. provided evidence that both phESCs (derived from blastocysts generated from activated unfertilized oocytes) and androgenetic haploid embryonic stem cells (ahESCs - derived from blastocysts generated via the injection of sperm into enucleated oocytes) developed a DNA hypomethylation signature similar to that observed in primordial germ cells following long-term in vitro culture. Therefore, both the phESCs and ahESCs exhibit an “imprint-free” DNA methylation status amenable to the uniparental generation of mice. However, as noted previously [3], crossing the same-sex reproduction barrier requires additional modifications, which come in the form of the deletion of specific imprinting regions.

In the hope of generating healthy and fertile mice via the injection of phESCs into MII oocytes, the authors assessed the deletion of additional regions (in combination with the H19 and Dlk-Dio2 intergenic regions) related to differentially imprinted genes discovered in previously generated bimaternal mice [3]. Encouragingly, the additional deletion of the Rasgrf1 imprinted region permitted the development of healthy and fertile bimaternal mice. However, when it came to dads turn, studies employing haESCs discovered the need to delete seven imprinted regions (NESPAS, Grb10, Igf2r, Snrpn, Kcnq1, Peg3, and Gnas) to allow the generation of live bipaternal mice via sperm coinjection into enucleated oocytes. However, while these findings do represent the first generation of a bipaternal mouse, all pups died shortly after birth. 

Final comparative analyses of bimaternal and bipaternal mice revealed that while two paternal genomes increased organ and body size, two maternal genomes decreased organ and body size, a finding that supports the genetic conflict theory of genomic imprinting [5], which states that paternally inherited imprinted genes extract nutrients from the mother during gestation.

The authors anticipate that their findings will help to explain why mammals normally only undergo sexual reproduction, and they now aim to improve their strategy by identifying further same-sex reproduction barriers, thereby allowing the birth of healthy and fertile mice from two fathers.

To read more about crossing the same-sex reproduction barrier in mammals and the successful generation of biparental mice; stay tuned to the Stem Cells Portal!


  1. Kono T, Obata Y, Wu Q, et al., Birth of parthenogenetic mice that can develop to adulthood. Nature 2004;428:860-4.
  2. Corley-Smith GE, Lim CJ, and Brandhorst BP, Production of androgenetic zebrafish (Danio rerio). Genetics 1996;142:1265-76.
  3. Li Z, Wan H, Feng G, et al., Birth of fertile bimaternal offspring following intracytoplasmic injection of parthenogenetic haploid embryonic stem cells. Cell Research 2016;26:135-8.
  4. Li ZK, Wang LY, Wang LB, et al., Generation of Bimaternal and Bipaternal Mice from Hypomethylated Haploid ESCs with Imprinting Region Deletions. Cell Stem Cell 2018;23:665-676.e4.
  5. Wilkins JF and Haig D, What good is genomic imprinting: the function of parent-specific gene expression. Nature Reviews Genetics 2003;4:359-68.