Mice produced by mitotic reprogramming of sperm injected into haploid parthenogenotes
Toru Suzuki, Maki Asami, Martin Hoffmann, Xin Lu, Miodrag Gužvić, Christoph A. Klein & Anthony C. F. Perry
Nature Communications 7, Article number: 12676 (2016)
DNA methylation Embryology Embryonic germ cells
Received: 12 August 2015 Accepted: 22 July 2016 Published online: 13 September 2016
Sperm are highly differentiated and the activities that reprogram them for embryonic development during fertilization have historically been considered unique to the oocyte. We here challenge this view and demonstrate that mouse embryos in the mitotic cell cycle can also directly reprogram sperm for full-term development. Developmentally incompetent haploid embryos (parthenogenotes) injected with sperm developed to produce healthy offspring at up to 24% of control rates, depending when in the embryonic cell cycle injection took place. This implies that most of the first embryonic cell cycle can be bypassed in sperm genome reprogramming for full development. Remodelling of histones and genomic 5′-methylcytosine and 5′-hydroxymethylcytosine following embryo injection were distinct from remodelling in fertilization and the resulting 2-cell embryos consistently possessed abnormal transcriptomes. These studies demonstrate plasticity in the reprogramming of terminally differentiated sperm nuclei and suggest that different epigenetic pathways or kinetics can establish totipotency.
We thank Animal Facility support staff for ensuring the welfare of animals used in this work, Mr. Manfred Meyer for excellent technical assistance, Dino Sharma (LSM Technical Services, Ltd.) for assistance with imaging and Drs M. VerMilyea and C. Tickle for incisive comments during manuscript preparation. We acknowledge Project Grant support from the Medical Research Council, UK (G1000839 and MR/N000080/1) and an EU Reintegration Grant (PIRG06-GA-2009-256408) to A.C.F.P.
Laboratory of Mammalian Molecular Embryology, Department of Biology and Biochemistry, University of Bath, Bath BA2 7AY, UK
Toru Suzuki, Maki Asami & Anthony C. F. Perry
Project Group Personalized Tumor Therapy, Fraunhofer Institute for Toxicology and Experimental Medicine ITEM, 93053 Regensburg, Germany
Martin Hoffmann & Christoph A. Klein
Experimental Medicine and Therapy Research, University of Regensburg, 93053 Regensburg, Germany
Xin Lu, Miodrag Gužvić & Christoph A. Klein
T.S. conceived and undertook core experiments. T.S., M.A. and A.C.F.P. conceived molecular and image analyses, which were performed by T.S. and M.A. M.G. performed microarray analysis. Bioinformatic data design and analysis was by M.H., X.L. and C.A.K. Other data analysis was by T.S., M.A. and A.C.F.P. A.C.F.P. wrote the manuscript with input from T.S. and M.A.
The authors declare no competing financial interests.
Correspondence to Christoph A. Klein or Anthony C. F. Perry.
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